Method and apparatus for selective treatment of biological tissue

ABSTRACT

An exemplary treatment system can be provided which can include a laser system configured to emit at least one laser beam, and an optical system configured to focus the laser beam(s) to a focal region at a selected distance from a surface of a tissue. The focal region can be configured to illuminate at least a portion of a target. The optical system can cause an irradiation energy transferred to the focal region of the laser beam(s) to (i) generate a plasma in a first region of the tissue adjacent to the target, and (ii) avoid a generation of a plasma in a second region of the tissue. The optical system has a numerical aperture that is in the range of about 0.5 to about 0.9. An exemplary method can also be provided to control such treatment system.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. Non Provisional patentapplication Ser. No. 15/853,318 filed Dec. 22, 2017, which issues asU.S. Pat. No. 10,973,578 on Apr. 13, 2021, which relates to and claimspriority from U.S. Provisional Patent Application Ser. No. 62/438,818filed on Dec. 23, 2016, the entire disclosures of which are incorporatedherein by reference in its entirety.

FIELD OF THE DISCLOSURE

Exemplary embodiments of the present disclosure relates to affectingpigmented biological tissue, and more particularly to methods andapparatus for selectively generating local plasma effects in pigmentedregions of such tissue.

BACKGROUND INFORMATION

Affecting biological tissue with optical (light) energy has gainedwidespread use over the past few decades. Optical energy is a form ofelectromagnetic energy. In the electromagnetic spectrum, optical energycan typically range from the infrared regime (longer wavelengths) to theultraviolet regime (shorter wavelengths). Treatment of biological tissuewith optical energy typically involves introducing the optical energyinto the tissue.

When optical energy is directed onto or into biological tissue, thereare three primary interactions that can occur. First, some portion ofthe energy may be reflected from the surface of the tissue. Suchreflection may be wavelength-dependent, and the fraction of reflectedenergy can be reduced, e.g., by appropriate selection of energywavelength, reducing variations in refractive index in the optical path(e.g., by using certain waveguide materials, providing a materialcoatings such as a gel on the tissue surface, etc.), and by selecting anappropriate angle of incidence of the beam on the tissue surface.

Optical energy can also be scattered by components in the tissue, whichleads to local changes in direction of a portion of the optical beamenergy. In some instances, scattering near the tissue surface can leadto a portion of the optical energy being scattered back out of thetissue surface (remission). If a tissue is relatively thin, some of theoptical energy may pass through the tissue and exit it, usually aftersome scattering has occurred.

The primary mechanism of interest for affecting tissue is absorption.Energy absorbed by tissue components can produce several effects. Forexample, energy absorption can lead to generation/enhancement ofvibrational modes of molecules and local heating effects. Localabsorption of high-intensity optical energy (generally over shorttimeframes) can even produce vaporization (or ablation) of tissue, wherelocal tissue components are broken down and converted to a gaseousstate. Such photo ablation can produce rapidly-expanding small vaporbubbles in the tissue, which can generate mechanical (as well asthermal) disruption of nearby tissue, or ejection of tissue fragmentsfrom the tissue surface. Optical energy absorption can also lead toelectron transitions, where electrons in an atom or molecule can beexcited to a higher (quantized) energy state. These absorptionmechanisms are linear, in which the absorption is substantiallyindependent of the intensity of the optical energy. The relative extentand efficiency of the absorption processes depend on many factors,including the nature of the absorbing material/component, thewavelength(s) of the optical energy, etc.

The three classes of optical energy sources typically used to affectbiological tissue are: 1) low power light sources such as lamps andlight-emitting diodes; 2) intense pulsed light (IPL) sources; and 3)lasers. IPL sources, such as flashlamps, generally providehigh-intensity pulses of non-collimated light beams having a range orspectrum of electromagnetic energy wavelengths. In contrast, lasersproduce intense collimated beams of energy that are composed of one ormore discrete wavelengths of coherent (in-phase) light. Lasers arepreferred for many types of optical treatments because the effects ofthe optical energy can be better controlled when tissue is irradiatedwith a known wavelength of light.

Lasers can provide optical energy as a continuous wave (CW), with acontinuous beam of energy, or as a series or sequence of energy pulses.Pulsed lasers can be generated by so-called Q-switching, mode locking,or in some cases by mechanical or electro-optical shuttering. Pulsedlasers are known in the art, and can be constructed to provide manycombinations of wavelength, pulse duration, and pulse intervals, as wellas different amounts of energy per pulse. Laser beams can also be shapedusing various waveguides and/or lenses, etc., to produce energy beamshaving various beam shapes, widths, and focal characteristics.Accordingly, certain lasers and their operating parameters can betailored to produce a broad range of effects in biological tissues.

It has been observed that application of light or optical energy ofcertain wavelengths can be strongly absorbed by chromophores, which arecertain molecules or portions thereof that are particularly efficientabsorbers of certain wavelengths of light. Chromophores can also governthe apparent color or appearance of certain tissue regions. Chromophoresin biological tissue are often located in certain pigmented cells orstructures, such as melanosomes or hair follicles. One commonchromophore in skin tissue is melanin, which determines the general skincolor of people. Hemoglobin in blood is another common biologicalchromophore. Chromophores in tissue can also be introduced from anexternal material, such as the light-absorbing nanoparticles of skintattoos or some topically-applied compounds. Other chromophores that maybe present in biological tissue can include, e.g., tattoo inks,sebaceous glands, subcutaneous fat, hair bulbs, lipids in cellmembranes, fat surrounding organs, blood vessels, and drug components.

A key concept in affecting biological tissue with optical energy isselective photothermolysis, where characteristics of optical energy usedto irradiate biological tissue are selected to provide preferentialabsorption of such energy by certain chromophores, with relativelylittle energy being absorbed by other regions of tissue that do notcontain the chromophore(s). Selective or preferential absorption of theoptical energy by chromophores can lead to local heating of the adjacenttissues, which can lead to thermal damage or necrosis of cells, physicalchanges in the heated tissue (e.g. coagulation, denaturation ofcollagen, etc.), and even vaporization of tissue.

Another factor affecting light/tissue interactions is the local thermalrelaxation time. For example, in selective photothermolysis, the thermalheating and tissue damage can be localized to chromophore-containingregions if the duration of local irradiation is relatively shortcompared to the local thermal relaxation time, which is a characteristictime in which a small source of heat will diffuse into the surroundingtissue. In contrast, longer local irradiation times can lead to morewidespread thermal damage arising from diffusion of heat away from thepreferential absorption site. General principles of selectivephotothermolysis are described, e.g., in R. R. Anderson et al.,Selective Photothermolysis: Precise Microsurgery by Selective Absorptionof Pulsed Radiation, Science, Vol. 220, No. 4596. pp. 524-527 (1983).

Irradiation of biological tissue with high-intensity optical energy canvaporize or ablate tissue, as noted previously. Certain ablative laserscan be used, e.g., to effectively cut tissue using light energy, and arecommon in many ophthalmic procedures such as corneal refractive surgery.For example, precise ablation of corneal tissue can be achieved usingnanosecond pulses of an ArF excimer laser, which emits light at awavelength of 193 nm. The very short pulse durations minimize thermaldamage away from the focused zones of direct irradiation.

Irradiation of tissue with high-intensity optical energy beams can alsolead to dielectric breakdown of tissue components and formation of aplasma. For example, focused laser pulses with very short durations(e.g., on the order of a few nanoseconds or less, often pico-second orfemtosecond pulse durations) and very high power densities (e.g.,10{circumflex over ( )}10 W/cm² or more) can produce an electric fieldstrength that is high enough to tear electrons away from atoms. At veryhigh local power densities, a plasma may be formed in the tissue, inwhich free electrons absorb even more energy and collide with otheratoms and molecules, ejecting more electrons (ionization) that alsoabsorb energy from the optical energy beam. This can produce a chainreaction that results in a plasma formation, which is often accompaniedby rapid local expansion and mechanical shockwaves in the tissue. Theseeffects can be used to generate certain types of damage and vaporizationof the tissue. Plasma formation is an example of a non-linear processthat depends on the presence of a high optical power density, and doesnot occur at the low optical power densities (expressed in units, e.g.,of W/cm²) typical of lamps, IPLs, and continuous wave lasers. A pulsedlaser source, typically focused to achieve sufficiently high powerdensity over very short time intervals, is used. Once a plasma isformed, the free electrons and ions within the plasma absorb incominglight, which sustains the plasma until the end of the laser pulse.

There are many known uses for plasma formation in materials. Forexample, pulsed laser etching within glass or other transparentmaterials is an industrial example of a plasma formed by dielectricbreakdown. In the medical field, posterior capsule cutting by a focusedQ-switched laser after cataract removal is an example of usingdielectric breakdown to generate a plasma that can locally vaporizetissue. More generally, dielectric breakdown at the focal spot of aQ-switched nanosecond or picosecond laser, which depends on powerdensity, is commonly used in ophthalmology to cut structures within theeye by locally scanning or moving the laser focal point within thestructure desired to be cut.

Plasma formation in tissue is often accompanied by a visible spark orflash of light and audible sound. Further absorption of the opticalenergy becomes non-linear in the plasma, where the absorption scales asthe fourth power of the beam intensity. The heated electrons and ionscan have extremely high temperatures on the order of 10{circumflex over( )}5 K and local pressures on the order of kilobars. Because of thevery high power densities and mechanisms of optical (or dielectric)breakdown, formation of plasma in tissue tends to be nonselective withrespect to the presence of chromophores.

Therefore, it may be desirable to provide method and apparatus that canselectively produce plasmas and associated damage mechanisms inbiological tissue, without generating excessive damage to non-targetedtissue or producing other undesirable side effects.

SUMMARY OF EXEMPLARY EMBODIMENTS OF THE DISCLOSURE

Exemplary embodiments of methods and apparatus can be provided for atreatment of biological tissue, for example, to selectively generatelocal plasma effects in pigmented regions of such tissue. The exemplaryembodiments of the methods and apparatus can facilitate a selectiveenergy absorption by pigmented or chromophore-containing structuresand/or regions within biological tissues (e.g., skin tissue) by focusinghighly-convergent electromagnetic radiation (EMR), e.g., optical energy,having appropriate wavelengths and other parameters onto regions withinthe tissue. This exemplary procedure can produce a sufficient selectiveabsorption of local energy densities in the tissue to result in aproduction of plasmas in the biological tissue, e.g., arising fromthermionic plasma initiation, which are selective tochromophore-containing tissue regions. Such localized plasmas candisrupt the pigment and/or chromophores while avoiding unwanted damageto surrounding unpigmented tissue and the overlying tissue. Such systemsand methods described herein can be used, e.g., to improve appearance ofskin tissue.

According to certain exemplary embodiments of the present disclosure, anapparatus can be provided that can include a radiation emitterarrangement configured to emit EMR, and an optical arrangementconfigured to direct the EMR onto the skin being treated and focus it toa focal region within the tissue. The EMR can be optical energypreferably having wavelengths in the near-infrared, visible, and/orultraviolet portions of the electromagnetic energy spectrum. The sourceof the EMR can be or include, e.g., a laser system or the like. Theapparatus can further include a housing and/or handpiece that cancontain these components and facilitate manipulation of the apparatusduring its use.

The EMR emitter can include, e.g., an EMR source such as one or morediode lasers, a fiber laser, or the like, and optionally a waveguide oroptical fiber configured to direct EMR from an external source. If theemitter arrangement includes a source of EMR, it can optionally alsoinclude a cooling arrangement configured to cool the EMR source(s) andprevent overheating of the source(s). A control arrangement can beprovided to control the operation of the emitter arrangement including,e.g., turning the EMR source on and off, controlling or varyingparameters of the EMR source such as average or peak power output, pulselength and duration, etc.

The EMR can have a wavelengths that is preferably greater than about 600nm, e.g., between about 600 nm and about 1100 nm. The selection of aparticular wavelength can be based on the absorption spectrum of one ormore particular chromophores. Wavelengths outside of this exemplaryrange can be used in certain exemplary embodiments, depending on thechromophores present, focusing properties of the optical energy beam(s),and/or parameters of the energy beam(s). For example, shorterwavelengths (e.g., less than about 600 nm) can be scatteredsignificantly within the skin tissue, and may lack sufficientpenetration depth to reach portions of the dermal layer with sufficientfluence and focus, but a high absorption coefficient for a particularchromophore may offset some of these effects.

The exemplary apparatus can include an optical arrangement configured tofocus the EMR in a highly convergent beam. For example, the opticalarrangement can include a focusing or converging lens arrangement havinga numerical aperture (NA) of about 0.5 or greater, e.g., between about0.5 and 0.9. The correspondingly large convergence angle of the EMR canprovide a high fluence and intensity in the focal region of the lenswith a lower fluence in the overlying tissue above the focal region.Such focal geometry can help reduce unwanted thermal damage in theoverlying tissue above the targeted tissue regions. The exemplaryoptical arrangement can further include a collimating lens arrangementconfigured to direct EMR from the emitting arrangement onto the focusinglens arrangement.

The exemplary apparatus can be configured to focus the EMR such that alocal intensity or power density of the optical energy in the focalregion is about 10{circumflex over ( )}10 W/cm² or more, for example,between about 10{circumflex over ( )}10 W/cm² and 10{circumflex over( )}11 W/cm² for optical energy having a wavelength of about 1060 nm. Incertain embodiments, the local power density can be lower, e.g., as lowas about 0{circumflex over ( )}8 W/cm², if other parameters such asabsorption efficiency (which depends in part on the chromophore and onwavelength of the optical energy) and energy density (which also dependsin part on pulse duration) are selected appropriately. An opticalarrangement can be provided to focus the EMR to a small spot size in thefocal region, e.g., a spot size (as measured in air with reducedscattering) between about 5 μm and about 100 μm. Such small focal spotsizes can facilitate generation of sufficiently high local powerdensities in the foal region. Somewhat smaller or larger spot sizes canbe used in certain exemplary embodiments, e.g., depending on otherfactors such as wavelength(s) of the optical energy and absorptioncoefficient by a particular chromophore at such wavelength(s).

The exemplary optical arrangement can also be configured to direct thefocal region of the EMR onto a location within the biological tissue(e.g., skin tissue or the like) that is at a depth below the surface ofbetween about 5 μm and 2000 μm (2 mm), e.g., between about 5 μm and 1000μm. This focal depth can correspond to a distance from a lower surfaceof the apparatus configured to contact the tissue surface and thelocation of the focal region. In further embodiments, the opticalarrangement can be configured to vary the depth of the focal regionand/or to provide a plurality of focal regions having different depthssimultaneously.

In further exemplary embodiments of the present disclosure, thepositions and/or orientations of the EMR emitter arrangement and/orcomponents of the optical arrangement can be controllable and/oradjustable relative to one another and/or relative to the tissue, suchthat the location and/or path of the focal region(s) in the tissue canbe varied. Such variation in the path of the focal region(s) can beprovided using optical arrangements having variable focal lengths,mechanical translators that can controllably vary the position of theoptical arrangement and/or EMR emitter arrangement relative to thetissue being treated, etc. Such exemplary variations in location of thefocal region(s) can facilitate treatment of larger volumes of the tissueby “scanning” the focal region(s) within the tissue, e.g., in a patternat a particular depth and/or at multiple depths. In certain exemplaryembodiments, a mechanical translator can be provided having scan speedsover an area of tissue to be treated that range from, e.g., about 5mm/sec to about 5 cm/sec.

In further exemplary embodiments of the present disclosure, a handpiececan be provided that is configured to be manually translated over thetissue at similar speeds. Sensor arrangements can be provided in suchmanual handpieces or in mechanically-translated devices to detectscanning speeds and affect parameters of the EMR source (such as EMRpulse duration, pulse frequency, pulse energy, etc.) and/or opticalarrangement based on such detection, e.g., to maintain a consistentrange of parameters such as local power density and local dwell timesduring treatment. For example, scanning speeds and focal region spotsizes can be selected to maintain a sufficiently small local dwell timeof the focal region at a location in the tissue (e.g. less than about1-2 ms) to avoid damaging unpigmented tissue.

In still further exemplary embodiments of the present disclosure, theexemplary optical arrangements can include a plurality of micro-lenses,e.g., convex lenses, plano-convex lenses, or the like. Each of themicro-lenses can have a large NA (e.g., between about 0.5 and 0.9). Themicro-lenses can be provided in an array, e.g., a square or hexagonalarray, to produce a plurality of focal regions in the dermal tissue in asimilar pattern. A width of the micro-lenses can be small, e.g., betweenabout 1 mm and 3 mm wide. Micro-lenses that are slightly wider ornarrower than this can also be provided in certain embodiments. In yetfurther exemplary embodiments of the present disclosure, themicro-lenses can include cylindrical lenses, for example, convexcylindrical lenses or plano-convex cylindrical lenses. A width of suchcylindrical micro-lenses can be small, e.g., between about 1 mm and 3 mmwide. A length of the cylindrical micro-lenses can be between, e.g.,about 5 mm and 5 cm. Other exemplary arrangements of a plurality ofsmall lenses can be used in further exemplary embodiments to generate aplurality of focal regions within the tissue, where such focal regionsmay be provided at the same or different depths (e.g., one or moremicro-lenses may have a different focal length than another micro-lens).

The exemplary radiation emitter arrangement and/or the exemplary opticalarrangement can be configured to direct a single wide beam of EMR overthe entire array of such micro-lenses or a portion thereof tosimultaneously generate a plurality of focal regions in the dermis. Infurther exemplary embodiments of the present disclosure, the radiationemitter arrangement and/or the optical arrangement can be configured todirect a plurality of smaller beams of EMR onto individual ones of themicro-lenses. Such multiple beams can be provided, e.g., by using aplurality of EMR sources (such as laser diodes), a beam splitter, or aplurality of waveguides, or by scanning a single beam over theindividual micro-lenses. If cylindrical micro-lenses are provided, oneor more beams of EMR can be scanned over such cylindrical lenses, e.g.,in a direction parallel to the longitudinal axis of such cylindricallenses.

In yet another exemplary embodiment of the present disclosure, a laserpulse having a relatively short duration on the order of, e.g., 10 μs,could be used to selectively heat the pigmented cells to liberate someelectrons via thermionic emission. A second optical energy pulse havingappropriate parameters, as described herein, including a pulse durationon the order of approximately 100 ns, can then be focused to irradiatethe same pigmented cells and “pump” the released electrons before theyrelax and rejoin the locally ionized atoms or molecules, therebyselectively forming a plasma at or proximal to the pigmented cells.Other pigmented targets located in the tissue, which may be external tocells, can also be irradiated to promote selective absorption of energyand plasma generation.

In still further exemplary embodiments of the present disclosure, amethod for selectively producing plasma in pigmented regions ofbiological tissue can be provided. The exemplary method can includedirecting and focusing electromagnetic radiation (e.g. optical energy)as described herein onto a plurality of focal regions within the tissueusing an optical arrangement, such that the optical energy isselectively absorbed by pigmented regions to generate some localionization via thermionic emission of electrons. The beam intensity andlocal dwell time should be sufficiently large to allow further energy tobe absorbed by the freed electrons, leading to further ionization by theexcited electrons and a subsequent chain reaction (sometimes referred toin physics literature as an “electron avalanche”) to locally form aplasma in the tissue

These and other objects, features and advantages of the presentdisclosure will become apparent upon reading the following detaileddescription of exemplary embodiments of the present disclosure, whentaken in conjunction with the appended drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects, features and advantages of the present disclosure willbecome apparent from the following detailed description taken inconjunction with the accompanying figures showing illustrativeembodiments, results and/or features of the exemplary embodiments of thepresent disclosure, in which:

FIG. 1 is a representative side view of one or more beams of radiationbeing focused into pigmented dermal tissue;

FIG. 2 is a cross-sectional side view of an exemplary apparatus inaccordance with exemplary embodiments of the present disclosure;

FIG. 3A is a side view of an arrangement of micro-lenses that can beused with certain exemplary embodiments of the present disclosure;

FIG. 3B is a top view of a first exemplary arrangement of themicro-lenses shown in FIG. 3A;

FIG. 3C is a top view of a second exemplary arrangement of themicro-lenses shown in FIG. 3A;

FIG. 3D is a top view of an exemplary arrangement of cylindricalmicro-lenses that can be used with certain exemplary embodiments of thepresent disclosure;

FIG. 3E is a perspective view of the exemplary arrangement ofcylindrical micro-lenses shown in FIG. 3D;

FIG. 3F is a side view of a further exemplary arrangement ofmicro-lenses that can be used with further exemplary embodiments of thepresent disclosure;

FIG. 4 is a schematic illustration of a scan pattern that can be usedwith exemplary embodiments of the present disclosure;

FIG. 5 shows a set of exemplary images, obtained at different times, ofa region of pig skin that was irradiated in accordance with certainexemplary embodiments of the present disclosure;

FIG. 6 shows a further set of exemplary images, obtained at differenttimes, of a region of a pig skin that was irradiated in accordance withfurther exemplary embodiments of the present disclosure;

FIG. 7A shows a further set of exemplary images, obtained at differenttimes, of a region of the pig skin that was irradiated over a range ofdepths in accordance with still further exemplary embodiments of thepresent disclosure;

FIG. 7B shows a further set of exemplary images, obtained at differenttimes, of the same region of pig skin shown in FIG. 7A that wasirradiated at deeper depths and 2 weeks after the first irradiation scanshown in FIG. 7A, in accordance with still further exemplary embodimentsof the present disclosure;

FIG. 8A shows a further set of exemplary images, obtained at differenttimes, of a region of pig skin that was irradiated in accordance withyet further exemplary embodiments of the present disclosure;

FIG. 8B illustrates images of a native skin test site at various stagesof treatment;

FIG. 8C is an exemplary image of a biopsy taken from the native skintest site shown in FIG. 8B taken by an electron microscope (EM);

FIG. 9 is a side cross-sectional view of an exemplary system for in vivoplasma detection in a tissue;

FIG. 10A is a plot of detected intensity spectra for irradiated tissuecontaining a melanin tattoo and tissue not tattooed with melanin;

FIG. 10B is a photomicrograph image of a section of the tissue samplecontaining melanin tattoo that was irradiated to obtain an intensityspectrum in FIG. 10A;

FIG. 11 is a plot of detected intensity spectra for irradiated tissuecontaining a carbon tattoo and tissue not tattooed with carbon;

FIG. 12 illustrates images of an exemplary test site at various stagesof treatment; and

FIG. 13 illustrates images of another exemplary test site at variousstages of another treatment.

Throughout the drawings, the same reference numerals and characters,unless otherwise stated, are used to denote like features, elements,components, or portions of the illustrated embodiments. Similar featuresmay thus be described by the same reference numerals, which indicate tothe skilled reader that exchanges of features between differentembodiments can be done unless otherwise explicitly stated. Moreover,while the present disclosure will now be described in detail withreference to the figures, it is done so in connection with theillustrative embodiments and is not limited by the particularembodiments illustrated in the figures. It is intended that changes andmodifications can be made to the described embodiments without departingfrom the true scope and spirit of the present disclosure as defined bythe appended claims.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Exemplary embodiments of the present disclosure can provide devices andmethods for selectively producing plasmas in biological tissue usingthermionic plasma initiation. Thermionic plasma initiation is athermophysical process, distinct from dielectric breakdown, that startswith heating of a material, liberating some thermal electrons. Theelectrons rapidly re-combine with the ionized molecules from which theycame, but under appropriate conditions they can also absorb incomingphotons from the laser/energy source to initiate a plasma. Thermionicplasma initiation is based in part on the mechanism of linear absorptionof light by a chromophore, and therefore can occur preferentially atsites of enhanced light absorption within a complex material such asliving tissue. Thermionic plasma initiation typically requires a highpower density, but this power density is usually much lower (e.g., byorders of magnitude) than that needed for dielectric breakdown.Therefore, in a heterogeneous material such as biological tissue, it ispossible for a pulsed laser to initiate thermionic plasma underappropriate conditions at the sites where a chromophore exists withinthe tissue.

Thermionic plasma initiation depends on the ability to liberate thermalelectrons from a chromophore and/or nearby molecules. Some moleculeshave weakly-bound electrons, which are more likely to be liberated whenthe material is heated, while molecules without weakly-bound electronsare less likely to liberate thermal electrons. In tissue, melanin is anexample of a chromophore with many weakly-bound electrons. Melanin isalso a strong chromophore over most of the optical spectrum. As such,melanin can be a preferential site for thermionic plasma formation whenexposed to sufficient power density, e.g., from a pulsed laser. Incontrast, plasma formation via dielectric breakdown does not depend onthe presence of a chromophore.

The efficacy of heating a chromophore to initiate a thermionic plasmadepends in part on energy density. The energy of a laser pulse is thetime integral of laser power. Femto- and pico-second laser pulses, whichcan initiate dielectric breakdown in very short time intervals, tend tohave an energy density that is below that needed for thermionic plasmainitiation because of the very short duration of the pulses. Longerpulse durations, even those in the microsecond domain (a million timeslonger than the femtosecond domain), can initiate thermionic plasmaformation under certain conditions when a suitable chromophore ispresent and the local power density is sufficiently high. The pulseenergy is preferably focused to a sufficient degree to provide asufficiently high local energy density in the tissue.

In certain embodiments of the present disclosure, electromagneticradiation (optical energy) such as, e.g., optical energy, at one or moreparticular wavelengths can be focused into the tissue, where the opticalenergy can optionally be pulsed and/or scanned, such that the opticalenergy is selectively absorbed by regions of the tissue containingchromophores. Such linear absorption of the optical energy can lead tolocal thermionic emission of electrons. With appropriate selection ofoptical energy parameters and beam geometry, further irradiation of thetissue region can lead to further energy absorption by the emittedelectrons, followed by local plasma formation and non-linear absorptionof energy. This procedure can produce intense heat, local expansion,stress waves such as strong acoustic or shockwaves, and/or chemicalreactions due to the plasma in the chromophore-containing region oftissue while generating relatively little energy absorption andassociated tissue damage in unpigmented regions.

General focusing of a laser beam below the surface of a material, suchas a living tissue, is known in the art as a technique for providing ahigh power density at the focal region, which can be adjusted to a givendepth below the material surface, e.g., using lenses and/or otheroptical components. For example, confocal laser microscope imaging ofliving human skin can provide detailed images of tissue at the depth ofa focal plane by scanning a laser beam focal point within the tissue.

In exemplary embodiments of the present disclosure, a laser-inducedplasma can be generated at a focal spot within tissue, based in part onselective absorption of the optical energy by chromophores that may bepresent; a pulsed laser beam can also be scanned or moved to produce aplurality of laser-induced plasmas as the focal spot changes locationwithin the tissue. Thermionic plasma formation requires a thresholdlevel of power and energy density at the site where a chromophore ispresent, as noted herein above. For thermionic plasma formation, a laserfocal region within the tissue can be scanned to initiate plasmaformation at a depth defined by the laser focus geometry, and suchplasma can be selectively formed only at sites where a chromophore ispresent. In this manner, a focused, scanned laser can be used toselectively damage chromophore sites within a well-defined region (e.g.,within one or more focal planes) inside the tissue.

Normal skin contains the chromophore melanin within the epidermis andhair follicles, and not within the dermis. Pathological conditions can,however, lead to melanin deposition in the dermis. These conditionsinclude post-inflammatory hyperpigmentation and melasma. Also notpresent in normal dermis, but present in some conditions, are exogenouschromophores, such as, e.g., pigment particles such as those in tattooinks. Various precipitates that may be present in tissues after drugtreatment can also act as chromophores. Such precipitates can include,e.g., gold, silver, tetracyclines, iron, amiodarone, chlorpromazine andothers. Other chromophores that may be present in biological tissueinclude, e.g., sebaceous glands, subcutaneous fat, hair bulbs, lipids incell membranes, fat surrounding organs, blood vessels, and certain drugcomponents.

For certain treatments and conditions, it can be desirable to effect theremoval of such chromophore particles in the dermis, without substantialharm to the overlying epidermis. Certain exemplary embodiments of thisdisclosure can provide methods and apparatus for such chromophoreremoval that include, e.g., scanning the focal spot or region of apulsed laser in one or more planes within the dermis and below theepidermis, under conditions that selectively generate thermionic plasmaformation at the sites of chromophore within the focal plane, withoutcausing such plasma formation within the overlying epidermis. Suchplasma formation can also generate local selective damage to the dermaltissue by physical and/or chemical mechanisms resulting from the plasmaformed at the site of chromophores in the dermis.

In practice, a scanned focal region or multiple focal regions of nearinfrared radiation capable of initiating thermionic plasma can beachieved up to a depth in skin of approximately 2 mm (2000 μm), asdescribed herein. The epidermis is nominally 0.1 mm thick (except forpalms and soles of the feet, which are generally thicker), such that afocal plane of a laser having appropriate electromagnetic, temporal, andoptical properties can be achieved within the dermis and below theepidermis, enabling thermionic plasma formation selectively at and/orproximal to chromophore sites in the dermis. After physical and/orchemical damage to the target chromophore sites in the skin or tissue,biological processes such as fluid transport, lymphatic uptake,phagocytosis and/or enzyme digestion can ultimately transport, remove ordigest the altered chromophore sites from the dermis. Also, biologicalcells containing or proximal to such chromophores that are irradiated togenerate a plasma can be damaged, modified, or killed, e.g., vianecrosis or apoptosis.

Shorter wavelengths of optical radiation (e.g., towards the violet andultraviolet end of the optical spectrum) tend to be scattered more bythe non-homogeneous structures of skin tissue than longer wavelengths.Such scattering can reduce the effective penetration depth of opticalenergy directed onto the tissue, and also inhibit focusing of a beam ofoptical energy into a small focal region as described herein. Ingeneral, the near-infrared portion of the optical spectrum (theso-called optical window) is capable of deeper penetration in to tissue,because these longer wavelengths undergo less scattering. When dermalmelanin is the target chromophore, wavelengths between about 600 and1100 nm are preferable for effective penetration into skin tissuetogether with good absorption by melanin. In certain embodiments,shorter wavelengths including ultraviolet, blue, green, and yellowregions of the optical spectrum could be used. The choice of one or morewavelengths of the optical energy can be based on, e.g., the desiredfocal depth(s) and the type(s) and concentrations of chromophore presentat one or more depths in the tissue.

The focal region size/width, quality, and length along the beam axis ofa focused laser beam directed into a biological tissue can be determinedby such factors as the laser beam divergence, laser mode structure,numerical aperture of the beam focusing optics, aberrations of thefocusing optics, coupling of the beam into tissue at the tissue surface(e.g. surface reflection and refraction effects), and optical scatteringproperties of the tissue.

“Rayleigh range” is the term used to describe the extent or length of afocal region along the optical axis. For example, the Rayleigh range candescribe the size of a focal region along the depth or z axis for a beamdirected into skin tissue. The Rayleigh range is affected by suchfactors, e.g., as the laser source divergence, wavelength of the opticalenergy, laser mode(s), original diameter of the beam prior toconvergence by optical elements, and numerical aperture of the focusingsystem. For example, a highly-convergent beam, where the outerboundaries of the beam converge at a relatively large angle as the beamreaches the focal region (and diverge at a similar angle beyond thefocal region), can exhibit relatively small Rayleigh length. A smallerfocused convergence angle would lead to a larger Rayleigh range, as thebeam converges and diverges slowly with respect to distance along thebeam axis. Typically, the Rayleigh range is several times larger thanthe transverse focal spot diameter.

By varying the focusing optical design and/or laser mode structure, awide variety of laser focal spots can be produce, which can becharacterized by geometrical parameters such as spot size or width(e.g., a characteristic dimension perpendicular to the axis of the beamin the focal region), and the Rayleigh range (e.g., a dimension of thefocal region along the longitudinal axis of the beam). The appropriatedimensions of a focal region for selectively initiating plasmas inbiological tissue (via thermionic emission) can be selected based onfactors such as the size of the chromophores being targeted, the pulseenergy and power of the optical energy source (which, together with thesize of the focal region will affect local power and energy densities),the Rayleigh range (which will further affect the range of depths thatcan be scanned within a volume of tissue in a particular time interval),etc. For example, dermal pigmentation, whether from melanin, tattoos ordrugs, is typically contained in cells that are themselves about 10 μmin diameter. Accordingly, a spot size/diameter of about this size orlarger may be desirable in certain embodiments, e.g., to irradiateentire cells to facilitate energy absorption by any chromophores withinthe cells. In other embodiments, a smaller spot size may be used, forexample, if small areas are being irradiated or if scanning speeds aresufficiently high.

An exemplary embodiment of the disclosure that describes plasmaformation in melanin-rich regions of the dermis will now be described insome detail. Further embodiments of the disclosure can produce selectiveplasma formation in other biological tissues, where the selectivity isgoverned by other chromophores that may be present in the tissue suchas, e.g., hemoglobin, certain tattoo inks, or the like.

An exemplary schematic side view of a section of skin tissue is shown inFIG. 1. The skin tissue includes a skin surface 100 and an upperepidermal layer 110, or epidermis, which is typically about 60-120 μmthick over much of the human body. The dermal thickness is about 2-3 mmover most of the body, but it can be slightly thicker in other parts ofthe body, such as the soles of the feet, and is particularly thin inother sites such as the eyelids. The underlying dermal layer 120, ordermis, extends from below the epidermis 110 to the deeper subcutaneousfat layer (not shown). A population of pigmented cells or regions 130that contain excessive amounts of melanin is shown in FIG. 1. Suchdermal pigmentation is typical of a dermal (or ‘deep’) melasma conditionin skin.

In exemplary embodiments of the present disclosure, a beam ofelectromagnetic radiation (optical energy) 150 (e.g., optical energy)can be focused into one or more focal regions 160 that can be locatedwithin the dermis 120. The optical energy 150 can be provided at one ormore appropriate wavelengths that can be preferentially absorbed bymelanin. The optical energy wavelength(s) can be selected to providesome degree of enhanced absorption of the energy by the pigmentedregions 130 relative to other unpigmented regions of the dermis 120.

In one exemplary embodiment of the present disclosure, a Yb fiber laserhaving a wavelength of 1060 nm can be used to generate the opticalenergy. In further embodiments, optical energy having wavelengthsbetween about 600 nm to 1100 nm may be provided with sufficient focusingand/or appropriate power and fluence, as described herein, to achievesufficient intensity and selectivity of absorption by chromophores inthe tissue. As described throughout the present specification, certaincombinations of optical energy wavelength, local power density orintensity, and local irradiation times can be combined to produce thedesired effects.

In further exemplary embodiments of the present disclosure, an apparatus200, schematically illustrated in a diagram of FIG. 2, can be providedto selectively generate plasma in tissue by irradiating it with opticalenergy 150, e.g., optical energy. For example, the apparatus 200 caninclude a radiation emitter arrangement 210, and an optical arrangementthat can be provided between the radiation emitter arrangement 210 andthe target tissue to be treated. For example, the optical arrangementcan include a first lens arrangement 220 and a second lens arrangement230. These exemplary components can optionally be provided in ahandpiece 250 or other housing or enclosure. The apparatus 200 canfurther include a contact surface configured to contact the surface 100of the tissue being treated. In one embodiment, the contact surface 240can include the second lens arrangement 230. In this embodiment, thecontact surface 240 may be convex, such that it provides localcompression of the underlying tissue when the apparatus 200 is placed onthe tissue being treated.

An actuator arrangement 260 can be provided to control the operation ofthe apparatus 200, e.g., to activate and/or turn off the emitterarrangement 210, control or adjust certain operational parameters of theapparatus 200, etc. A power source (not shown) for the radiation emitterarrangement 210 can be provided. For example, the power source caninclude a battery provided within the handpiece 250, an electrical cordor other conductive connection provided between the emitter arrangement210 and an external power source (e.g. an electrical outlet or thelike), etc.

The radiation emitter arrangement 210 can include, e.g., one or moreoptical energy sources (including a pulsed laser such as, e.g.,flashlamp-pumped pulsed lasers, Q-switched lasers, mode-locked pulsedlasers, a Q-switched fiber laser, or a diode-pump solid-state laser).These lasers can sometimes be powered by a diode laser), optical fibers,waveguides, or other components configured to generate and/or emitoptical energy 150 and direct it toward or onto the optical arrangement220, e.g., onto the first lens arrangement 220. In further exemplaryembodiments, the radiation emitter arrangement 210 can include distalends of one or more waveguides (e.g., optical fibers) (not shown), wherethe waveguides can be configured or adapted to direct optical energy 150from an external optical energy source, such as a laser (not shown),toward or onto the first lens arrangement 220.

In further exemplary embodiments of the present disclosure, theelectromagnetic radiation (optical energy) 150 can be focused into oneor more focal regions 160 that can be located within the tissue 120, asshown schematically in FIGS. 1 and 2. The exemplary optical arrangementcan be configured to provide one or more highly-convergent beams ofoptical energy 150, where each such beam can be emitted from a lowerportion of the apparatus 200 and converge to a narrower focal region 160located at a particular distance below the lower surface of theapparatus 200, e.g., below the lower surface of the contact surface 240.Such convergence of the optical energy 150 can produce a high localfluence and intensity within the focal region 160, while irradiating theoverlying tissue (e.g. epidermis 110 and upper portion of the dermis 120in FIG. 1) at a lower fluence. In certain embodiments, the focal region160 can be located at or very close to the lower surface of the contactsurface 240, which can thus provide high-intensity irradiation of thesurface region of the tissue contacting the contact surface 240.

The first lens arrangement 220 can be adapted and/or configured todirect optical energy 150 from the emitter arrangement 210 towards oronto the second lens arrangement 230. The first lens arrangement 220 caninclude, e.g., one or more lenses, reflectors, partially- orfully-silvered mirrors, prisms, and/or beam splitters. For example, thefirst lens arrangement 220 can be configured to collimate or align theoptical energy 150 emitted from the emitter arrangement 210 onto thesecond lens arrangement 230, as shown in FIG. 2. The first lensarrangement 220 can include, e.g., an objective lens or the like.

The second lens arrangement 230 can be configured and/or adapted toreceive optical energy 150 from the first lens arrangement 220, anddirect it into one or more focal zones 160 within the dermis 120, asshown in FIG. 1, or into other tissues. For example, the first lensarrangement 220 can be a collimating lens, and the second lensarrangement 230 can serve as a focusing lens that includes, e.g., asingle objective lens as shown in FIG. 2, one or more plano-convexlenses or cylindrical lenses, or the like. Various exemplary opticalarrangements can be used to produce one or more focal regions 160. Someembodiments of such optical arrangements are described in more detailherein below. In certain embodiments, a single optical arrangement(which may include 2 or more lenses, reflectors, prisms, or the like)may be used to focus the optical energy 150 into a focal region 160.

As shown in FIG. 2, the highly-convergent beam of optical energy 150 isrelatively “spread out” as it is passes through the contact surface 240(e.g., as it enters the surface 100 of the skin tissue when theapparatus 200 is placed on the skin to irradiate it). Geometrical,temporal, and power characteristics of the optical energy 150 can beselected as described herein, such that the fluence and intensity of theoptical energy 150 at and near the skin surface 100 are sufficiently lowto avoid unwanted heating and damage to the tissue overlying the focalregion 160. The optical energy 150 can then be focused to a sufficientintensity and fluence within the focal zone 160 to facilitatesignificant absorption of the optical energy 150 by pigmented regions130 within or proximal to the focal region 160. In this manner,exemplary embodiments of the present invention can target pigmentedregions 130 within the dermis 120 to selectively heat them, and tofurther generate a plasma, without generating unwanted damage to theoverlying tissue and surrounding unpigmented tissue.

Exemplary beam convergent angles of about 70-80 degrees are illustratedin FIGS. 1 and 2. In general, the convergent angle can be about 40degrees or greater, e.g., even about 90 degrees or larger. Suchnon-narrow convergence angles can generate a large local intensity andfluence of optical energy 150 at the focal region 160, while thecorresponding fluence in the overlying (and underlying) tissue regionsmay be lower due to the beam convergence and divergence. It should beunderstood that other convergence angles are possible, and are withinthe scope of the present disclosure.

Accordingly, the effective numerical aperture (NA) of the second lensarrangement 230 is preferably large, e.g., greater than about 0.5, suchas between about 0.5 and 0.9, when the apparatus 200 is used to generatea plasma in tissue regions below the tissue surface. The numericalaperture NA is generally defined in optics as NA=n sin θ, where n is therefractive index of the medium in which the lens is working, and θ isone-half of the convergence or divergence angle of the beam. The opticalenergy 150 enters the lens through surrounding air, which has an indexof refraction of about 1. Thus, an exemplary convergent half-angle θ ofthe beam of optical energy towards the focal region 160, correspondingto a NA value between about 0.5 and 0.9, can be between about 30 and 65degrees. Thus, the exemplary range of the total convergence angle can bebetween about 60 and 130 degrees. The NA may be smaller, e.g., whensurface regions of the tissue are being irradiated, as there is littleor no overlying tissue that could be damaged inadvertently.

Larger values of the effective NA can provide a larger convergenceangle, and a corresponding greater difference in the local beamintensity and fluence between the tissue surface 100 and the focalregion 160. Accordingly, a larger NA value can provide a greater “safetymargin” by providing less intense irradiation levels to the overlyingtissue than to the pigmented regions 130, thereby reducing thelikelihood of generating thermal damage in the overlying tissue.However, a larger NA value can decrease the size of the focal region 160relative to the area of the incoming optical energy beam, which canthereby irradiate a relatively smaller treatment volume of pigmentedtissue within the dermis 120. Such smaller treatment volumes can reducethe efficiency of treating large areas of skin in a reasonable time.Exemplary NA values between about 0.5 and 0.9 can thus provide areasonable compromise between safety factor and treatment efficiency,although slightly larger or smaller values of the NA may be used incertain embodiments (e.g., by adjusting other system parametersappropriately, such as beam power, scanning speed, etc.).

A width of the focal region 160 (e.g., a “spot size”) can be small,e.g., less than about 100 μm, for example, less than 50 μm, or less than10 μm. In general, the focal region can be defined as the volumetricregion in which the optical energy 150 is present at a highestintensity. For example, the focal region 160 may not be present as anidealized spot because of such factors as scattering of the opticalenergy 150 within the tissue, aberrations or nonidealities in theoptical components (e.g. lenses and/or reflectors), variations in thepath of the incident rays of optical energy 150, etc. Further, the focalregion 160 can be spread over a small range of depths within the tissue,as shown schematically in FIGS. 1 and 2. In general, the size andlocation of the focal region relative to the apparatus 200 can bedetermined or selected based on properties and configuration of theoptical arrangement (e.g., the first and second lens arrangements 220,230), the characteristics of the optical energy 150 provided by theemitting arrangement 210, and optical properties of the tissue beingtreated.

In certain exemplary embodiments, the width of the focal region 160(e.g., the “spot size”) can be less than 50 μm, e.g., smaller than 10μm. The focal spot diameter or spot size can be generally defined as thesmallest diameter of an actual focused (e.g., convergent) beam, whichconverges as it enters the focal region and diverges as it exits thefocal region. By varying parameters, components, and configuration ofthe focusing optical arrangement and/or laser mode structure, a widevariety of laser focal spot sizes can be produced. A minimum theoreticalbeam focal spot size can be determined by optical diffraction and thenumber of optical modes present in the laser output, and is referred toas the diffraction-limited focal spot size. Typically, this minimum spotsize is several times the wavelength of the corresponding light. Forexample, using a 1060 nm single-mode fiber laser (which has goodfocusing properties), the diffraction-limited focal spot diameter for anoptical system focusing into the dermis would be less than about 5 μm.In practice, effects such as optical scattering in the tissue andaberrations of optical components produce focal spots greater than thisdiffraction-limited minimum.

Dermal pigmentation, such as melanin, tattoo inks, or drug components,is typically contained within cells, which are themselves about 10 μm indiameter. The laser focal spot diameter can be greater than or less thanthe diameter of such target cells, depending on desired results and thelaser/optics being used. A laser having lower power output can befocused to relatively smaller sizes to achieve sufficient energy andpower densities. Alternatively, a higher-powered laser canthermionically initiate a plasma with a relatively larger spot size.Such larger spot sizes can, e.g., be scanned over a given area or volumeof tissue in a shorter time to selectively produce plasma at chromophoresites in the volume of tissue.

For example, a theoretical lower for the spot size can be approximatedas 1.22λ/NA, where λ is the wavelength of the electromagnetic radiationand NA is the numerical aperture of a lens. For a wavelength of about1060 nm and a NA of 0.5, the theoretical minimum spot size is about 2.6microns. The actual spot size (or width of the focal region 160) can beselected as being small enough to provide a sufficiently high powerdensity or density of optical energy 150 in the focal zone 160(sufficient to initiate thermionic emission and subsequently generate aplasma). For example, for a given pulsed laser source having aparticular pulse duration and peak (or average) pulse power (or totalpulse energy), a smaller spot size will result in a larger intensity (orpower density). Based on geometrical considerations, the power andenergy densities of a particular optical beam pulse in a focal regionare inversely proportional to the square of the focal spot size (or,inversely proportional to the focal spot area).

For a particular exemplary NA value of the focusing lens arrangement230, the beam radius at the surface can be estimated as the focal depthmultiplied by the tangent of the half-angle of convergence provided bythe focusing lens. As an example, an NA value of 0.5 corresponds to aconvergence half-angle of about 30 degrees, for which the tangent is0.577. For an exemplary focal depth of 200 microns into the tissue, theradius of the converging optical energy beam at the skin surface 100 isabout 115 microns (0.577×200), such that the total beam width at thesurface is about 230 microns. The local intensity is inverselyproportional to the local cross-sectional area of the beam for aparticular beam power. Accordingly, for a spot size (focal region width)of 20 microns, the ratio of fluence at the focal region to that at theskin surface (ignoring absorption between the surface and focal spot) isabout (230/20)², or about 130:1. The actual fluence ratio may besomewhat less due to absorption of some of the optical energy betweenthe tissue surface and the focal region. Nevertheless, this exemplarycalculation indicates that a focusing lens having a high NA can generatea relatively low intensity in the surface regions of the tissue ascompared to the intensity in the focal region.

In further exemplary embodiments of the present disclosure, a pluralityof such focal regions 160 can be generated simultaneously by theexemplary apparatus. In still further embodiments, the focal region(s)160 may be scanned or traversed through the portions of tissuecontaining chromophores to irradiate larger volumes of the tissue in areasonable time, as described in more detail herein.

In certain exemplary embodiments for selectively generating plasma inskin tissue exhibiting dermal melasma, the depth of the focal region 160below the skin surface 100 can be up to about 2000 μm. In some exemplaryembodiments of the present disclosure, an exemplary focal depth belowthe skin (or other tissue) surface can be between about 5 μm and about1000 μm, which permits a range of treatment depths that can be achievedwithout excessive scattering or absorption of energy above the focalregion 160. In further exemplary embodiments of the present disclosure,the depth of the focal region 160 can be between about 120 μm and 400μm, e.g., between about 150 μm and 300 μm. These latter exemplary depthranges can generally correspond to the observed depths of pigmentedregions 130 in skin that exhibits dermal melasma. The exemplary focaldepth can correspond to a distance from the bottom of the apparatus 200(e.g., the lower surface of the contact surface 240) and the focalregion 160 of the optical energy 150, because the contact surface 240may flatten out the underlying tissue when placed on the skin surface100. Accordingly, the depth of the focal region 160 within the skin maybe selected or controlled based on a configuration of the opticalarrangements 220,230 within the housing 250.

In various exemplary embodiments of the present disclosure, the opticalenergy 150 can be collimated (e.g., rays within the optical energy beamare substantially parallel to one another), convergent, or divergentbetween the first lens arrangement 220 and second lens arrangement 230.In still further exemplary embodiments, the radiation emitterarrangement 210 and/or components of the optical arrangement (e.g., thefirst lens arrangement 220 and/or the second lens arrangement 230) canbe controllable or adjustable such that the path of the optical energy150 can be varied. Such exemplary variation in the path of the opticalenergy 150 can provide corresponding variations in the depth, width,and/or location of the focal region 160 within the tissue beingirradiated when the apparatus is held stationary with respect to thetissue.

For example, the position and/or angle of the optical energy 150 can beshifted relative to the optical axis of a lens in the second lensarrangement 230. Alternatively or additionally, the convergence ordivergence of the optical energy 150 entering or within the opticalarrangement can be varied. Such variations in the optical energygeometry and/or path can provide variations in the depth and/or lateralposition of the focal region(s) 160. In this manner, larger volumes ofthe tissue can be irradiated while the apparatus 200 is held stationaryover the area of tissue being treated. Such exemplary variation of thefocus region characteristics can facilitate treatment of a plurality ofdepth ranges and/or locations within the tissue containing chromophores(including, but not limited to, pigmented cells or vascular structures).

Exemplary adjustment and/or alteration of the geometry and/or path ofthe optical energy 150 can be achieved, e.g., using one or moretranslators, movable mirrors, beam splitters and/or prisms, or the like,which may be coupled to the radiation emitter arrangement 210, the firstlens arrangement 220, and/or the second lens arrangement 230. In furtherembodiments, the apparatus 200 can be translated over the area of tissuebeing treated to irradiate larger volumes of the tissue at one or moredepths, thereby targeting a greater number of chromophore-containingregions within a larger tissue volume. Such translation can be doneusing a controllable translating apparatus, or alternatively suchtranslation can be done manually, e.g., by having a user hold theapparatus in hand and moving it over the tissue surface. Combinations ofmanual and automated translational movement can be provided in stillfurther embodiments.

In further exemplary embodiments, the exemplary apparatus 200 in FIG. 2can include a sensor arrangement for detecting the velocity and/orposition of the apparatus 200 relative to the tissue being treated,e.g., while it is manually scanned over the tissue, and the data sent toa control arrangement (not shown) that can affect output parameters ofthe laser and/or translating apparatus, if present. For example, amechanical or optical motion sensing arrangement, similar to that foundin a computer mouse device, can be used to track velocity and/orposition of the apparatus 200 during use. Feedback control based onvelocity and/or position data can be used, e.g., to affect parameterssuch as pulse duration, pulse frequency, pulse energy, etc. Appropriatecontrols can be implemented based on application of conventional controltechniques, together with the various parameter ranges and phenomenadescribed herein, to avoid unwanted tissue damage including, but notlimited to, plasma formation away from chromophores, or excessive energyirradiation of overlying tissues (e.g. in the epidermis). Similartracking devices have been successfully employed for device control inhand-scanned fractional lasers used for dermatological treatments (e.g.,Reliant Fraxel® laser systems).

In one embodiment of the present disclosure, the second lens arrangement230 can include a plurality of micro-lenses 300, e.g., as provided in aschematic side view of the exemplary configuration illustrated in FIG.3A. For example, the micro-lenses 300 can include any conventional typeof convergent lenses, e.g., convex lenses, or plano-convex lenses suchas those shown in FIG. 3A. The micro-lenses 300 can be configured tofocus optical energy 150 into a plurality of focal regions 160 withinthe underlying dermis 120 or other tissue, as illustrated in FIG. 3A.

Each of the micro-lenses can have a large NA (e.g., between about 0.5and 0.9), such that the optical energy 150 converges from a relativelywide area at or near the surface 100 of the skin or other tissue (with arelatively low intensity/power density and fluence) to a small width(with higher intensity/power density and fluence) in the focal region160 within the dermis 120 or other tissue. Such optical properties canprovide a sufficient intensity of optical energy 150 within the focalregion 160 to initiate plasma formation, while avoiding areas or volumesof high intensity away from the volume of tissue containing chromophores(e.g. pigmented cells 130), thereby reducing likelihood of damagingoverlying, underlying, and/or adjacent volumes of unpigmented skintissue.

The micro-lenses 300 can be provided in any geometric pattern such as,but not limited to, a substantially square or rectangular array, such asthat shown in the top view of such exemplary configuration in FIG. 3B.According to further exemplary embodiments of the present disclosure,the micro-lenses 300 can be provided in a hexagonal array, as shown inFIG. 3C. Other exemplary patterns and/or shapes of the micro-lenses 300can be provided in still further exemplary embodiments. A width of themicro-lenses 300 can be small, e.g., between about 1 mm and 3 mm wide.The exemplary micro-lenses 300 that are slightly wider or narrower thanthis can also be provided in certain exemplary embodiments. The array ofmicro-lenses 300 can itself be moved or scanned, to provide a densearray (or a continuous region) of tissue volume irradiated by focalspots over time, in the focal plane(s) of the lens array.

In additional embodiments of the present disclosure, the radiationemitter arrangement 210 and/or the first lens arrangement 220 can beconfigured to direct a single wide beam of optical energy 150 (such as,e.g., that shown in FIG. 2) over the entire array of micro-lenses 300 ora substantial portion thereof. Such exemplary configuration can generatea plurality of focal regions 160 in the tissue simultaneously. Infurther exemplary embodiments, the radiation emitter arrangement 210and/or the first lens arrangement 220 can be configured to direct aplurality of smaller beams of optical energy 150 onto individual ones ofthe micro-lenses 300. According to still further exemplary embodiments,the radiation emitter arrangement 210 and/or the first lens arrangement220 can be configured to direct one or more smaller beams of opticalenergy 150 onto a portion of the array of micro-lenses 300, e.g. onto asingle micro-lens or a plurality of the micro-lenses 300, and thesmaller beam(s) can be scanned over the array of the micro-lenses 300,such that a plurality of the focal regions 160 can be generatedsequentially or non-simultaneously in the tissue being irradiated.

In yet further exemplary embodiments of the present disclosure, themicro-lenses 300 can include cylindrical lenses, for example, convexcylindrical lenses or plano-convex cylindrical lenses, e.g., as shown inan exemplary top view in FIG. 3D and exemplary angled view in FIG. 3E.In the context used herein, ‘cylindrical’ does not necessarily requirethe rounded surface of the lens to be circular; it may have anelliptical or other smooth but non-circular profile in certainembodiments. Such cylindrical lenses can have a uniform profile in anycross-section that is perpendicular to the longitudinal axis of thelens.

A width of the cylindrical micro-lenses 300 can be small, e.g., betweenabout 1 mm and 3 mm wide. The length of the cylindrical micro-lenses 300can be between about 5 mm and 5 cm, e.g., between about 5 mm and about 2cm. This width and length can be selected based on such factors as thetotal power emitted by the radiation emitter arrangement 210, theoverall size of the array of micro-lenses 300, etc. In certain exemplaryembodiments, cylindrical micro-lenses 300 that are slightly shorter orlonger and/or slightly narrower or wider can be provided.

In certain exemplary embodiments of the present disclosure, any of theexemplary arrays of the micro-lenses 300 can be provided on (or formedas part of) the contact surface 240, as illustrated in FIG. 3E. Suchconfiguration can facilitate placement of the micro-lenses 300 close tothe tissue surface, and also facilitate a more precise depth of thefocal regions 160 within the tissue, e.g., when the contact surface 240contacts the tissue surface during use.

In further exemplary embodiments of the present disclosure, theradiation emitter arrangement 210 and/or the first lens arrangement 220can be configured to direct a single wide beam of optical energy 150(such as that shown in FIG. 2) over the entire array of cylindricalmicro-lenses 300 or a substantial portion thereof. Such exemplaryconfiguration can simultaneously generate and/or produce a plurality ofthe focal regions 160 within the tissue 120 that are elongated in onedirection (e.g. along the longitudinal axis of the cylindricalmicro-lenses 300) and narrow (e.g., less than about 100 μm wide, lessthan about 50 μm wide, or even less than about 10 μm wide) in adirection orthogonal to the longitudinal axis of the cylindricalmicro-lenses 300. Such “line-focused” optical energy 150 can be used tomore efficiently irradiate larger volumes of the tissue, e.g., when theexemplary apparatus 200 is scanned over the area of tissue beingtreated, for example, in a direction substantially orthogonal to (oroptionally at some other angle to) the longitudinal axis of thecylindrical micro-lenses 300.

According to yet additional exemplary embodiments of the presentdisclosure, the radiation emitter arrangement 210 and/or the first lensarrangement 220 can be configured to direct one or more smaller beams ofoptical energy 150 onto one or more of the cylindrical micro-lenses 300.For example, the optical energy 150 can be directed onto one or morecylindrical micro-lenses 300, e.g., over an elongated area 320 such asthat shown in FIG. 3D. The radiation emitter arrangement 210 and/or thefirst lens arrangement 220 can be further configured to scan or traversethe irradiated area 320 over the cylindrical micro-lenses 300 (forexample, using one or more movable mirrors, prisms, waveguides, or thelike in the optical arrangement), e.g., along the longitudinaldirections indicated by the arrows shown in FIGS. 3D and 3E (or back andforth along such direction), such that a plurality of the elongatedfocal regions 160 are progressively generated in the dermis 120 duringthe scan. Such scanning of the optical energy 150 can produce anirradiated focal region 160 having a shape of an extended line withinthe dermis 120. The apparatus 200 can also be traversed laterally overthe region of skin being treated, e.g., in a direction not parallel tothe longitudinal axes of the cylindrical micro-lenses 300, during theirradiation such that the elongated focal regions 160 can travel throughthe dermis 120 and irradiate a larger volume of tissue. For example, asdescribed herein such lateral traversal can be between about 5 mm/secand 5 cm/sec. The scanning speed of the optical energy beam along theaxes of the cylindrical can be larger, e.g., greater than about 10cm/sec, to provide a more uniform irradiation of such larger volumes oftissue. The scan rate of the optical energy 150 along the cylindricallens axes, traversal speed of the apparatus 200 over the skin, power ofthe optical energy emitter arrangement 210, and width of the focalregion 160 can be selected to provide a local fluence generated withinportions of the dermis 120 by the elongated focal region 160 that iswithin the exemplary fluence ranges described herein.

In yet further exemplary embodiment of the present disclosure, some ofthe cylindrical or spherical micro-lenses 300 can have different NAvalues, different sizes or radii, and/or different effective focallengths, e.g., as shown in the exemplary schematic diagram in FIG. 3F.The different focal depths of the micro-lenses 300 below the skinsurface 100 can be, e.g., between about 120 μm and 400 μm, for example,between about 150 μm and 300 μm. Such exemplary variations in the focallengths can produce focal regions 160 at different depths, which canresult in irradiation of larger volumes of the dermis 120 when theexemplary apparatus 200 is translated over the area of skin beingtreated, thereby targeting a greater number of pigmented cells 130 thatmay be present (e.g., irradiating both shallower and deeper pigmentedcells 130 in the dermis 120).

In one exemplary embodiment, the radiation emitter arrangement 210and/or the first lens arrangement 220 can be further configured to varythe incident angle of the optical energy 150 as it is directed onto thesecond lens arrangement 230 or the micro-lens array 300. Such variationin angle can direct the focal region 160 from a plurality of pulses intoa plurality of locations without translating the apparatus 200 or anylenses with respect to the tissue 100. Such variation of the incidentangle can provide more uniform irradiation of the tissue duringscanning, by irradiating a plurality of spots for each fixed location ofthe apparatus 200 and/or lenses with respect to the tissue 100.

In another exemplary embodiment of the disclosure, the first lensarrangement 220, the second lens arrangement 230, and/or the micro-lensarray 300 can be configured (e.g. using actuators or the like) tocontrollably vary the focal distance between the apparatus 200 and thefocal region 160. Such variation in the focal distance can direct thefocal region 160 from a plurality of pulses to a plurality of depths ata single location without translating the apparatus 200 or any lenseswith respect to the tissue 100. This type of scanning pattern can beused to irradiate multiple depths (z-values) at each location during ascanning procedure before advancing the focal region to another (x-y)location on the tissue. The sequential depths irradiated at a locationcan vary from deeper to shallower in one embodiment (by decreasing thefocal distance while irradiating a particular x-y location).Alternatively, the focal distance can be varied from shallower to deeper(by increasing the focal distance while irradiating a particular x-ylocation). Either depth sequence may be used, and selected based onother factors such as the effect of irradiation on deeper or overlyingregions of tissue, the depth distribution of chromophores in the tissue,etc. These embodiments in which the focal depth is varied at a singlex-y location represent an alternative to the exemplary scan patternillustrated in FIG. 4, in which the focal region 160 is scanned in araster pattern or the like at a fixed focal depth (e.g., within a singlex-y plane) and then the focal depth is varied to scan another x-y planeat a different depth.

The window or contact surface 240, if present, can be configured and/orstructured to contact the surface 100 of the area of skin being treated.The lower surface of the window 240 can be substantially planar, or itmay be convex or concave in further embodiments. The window 240 canprovide certain benefits during operation of the apparatus 200. Forexample, the window 240 can facilitate precise positioning of the firstand second optical arrangements 220, 230 relative to the skin surface100, which can facilitate accurate control, selection and/or variationof the depth(s) of the focal region(s) 160 within the skin.

The window 240 can further stabilize the soft skin tissue while it isbeing irradiated by the apparatus 200, which can facilitate control anduniformity of the irradiation profile. Pressure provided by the window240 on the skin surface 100 can also blanche (or remove some blood from)the volume of skin tissue being irradiated, thereby reducing the amountof pigmented structures present locally (e.g. blood-filled vesselscontaining hemoglobin). Such blanching can facilitate increasedselectivity of absorption of the optical energy 150 by pigmented cells130 while reducing a risk of unwanted damage to blood vessels.

In exemplary embodiments of the disclosure, the window 240 can becooled, e.g., by pre-cooling it prior to using the apparatus 200 or byactive cooling using a conventional cooling arrangement (e.g. a Peltierdevice, a conductive cold conduit, or the like). In other embodiments,the tissue itself can be cooled prior to irradiation, e.g., using acryospray or contact cooling with a cold object. Such cooling canfacilitate protection of upper portions of the tissue from unwanteddamage and/or pain sensation while the pigmented regions within thetissue are being irradiated to produce a plasma therein.

A refractive index coupling fluid or gel can be used to reduce opticallosses and aberrations as the laser beam(s) pass from the opticalfocusing apparatus into the tissue. For example, human skin has arefractive index of about 1.5 in the optical region of 600-1100 nm, andits surface is rough, such that a beam of light encounters the skin at arange of local incidence angles. Air has a refractive index of 1.0, suchthat reflection and refraction is high. By applying a fluid or gelmaterial with refractive index closer to that of the skin, the lossesand aberrations are less. An analogous situation and solution relatingto a use of focused lasers for reflectance confocal microscopy of skinwas described, e.g., in M. Rajadhyaksha et al., “In vivo confocalscanning laser microscopy of human skin: melanin provides strongcontrast,” J Invest Dermatol., 104(6), 946-52 (June 1995).

According to certain exemplary embodiments of the present disclosure,the window 240 can be provided as part of the second lens arrangement230. For example, the second lens arrangement 230 can include a singleplano-convex lens or a plurality of plano-convex lenses, such as thoseshown in FIGS. 3A and 3D. Such lenses can be affixed to or formed aspart of the window 240. The lower (planar) surface of such lenses canprovide the benefits of the window 240 as described herein, e.g.,precise positioning of the second lens arrangement 230 relative to theskin surface 100 to control depth of the focal regions 160.

The actuator arrangement 260 can be configured to activate and/orcontrol the radiation emitter arrangement 210 and/or an external opticalenergy source that provides radiation to the radiation emitterarrangement 210, such that the irradiation characteristics of an area oftissue by the optical energy 150 can be controlled. The radiationemitter arrangement 210 and/or the exemplary apparatus 200 can furtherinclude a conventional control arrangement (not shown) that can beconfigured to control and/or adjust the properties of the optical energy150 directed onto the tissue being treated.

For example, the apparatus 200 can include one or more sensors (notshown) configured to detect contact of the apparatus 200 with the skinsurface 100 and/or speed or displacement of the apparatus 200 over theskin surface 100 during use. Optical sensors can also be provided todetect the present of sparks or flashes that indicate generation of aplasma in the irradiated tissue. Such exemplary sensors can generatesignals capable of varying properties of the optical energy 150, e.g.,by varying the power emitted by the radiation emitter arrangement 210based on the translational speed of the apparatus 200, by turning offthe source(s) of optical energy 150 when the apparatus 150 is stationaryrelative to the tissue surface 100, etc. Such sensors and controlarrangements can be provided as a safety feature, e.g. to preventexcessive irradiation and unwanted damage to the tissue being treated,and are generally known in the art. For example, an optical sensor canbe used to adjust parameters of the optical energy source for a givenfocal geometry and scanning/translational speed such that plasmageneration in pigmented regions is just initiated. Such control canavoid excessive plasma formation and/or formation of plasma in tissuethat does not contain chromophores. Further variations of suchconventional sensing and/or control arrangements can be used inembodiments of the present disclosure. In general, local irradiationtimes (or “dwell times”) should be sufficiently long to selectivelygenerate a plasma in the tissue following the initial linear energyabsorption by the chromophores. The dwell time can be estimated, e.g.,as the time it takes the full width of the focal region to pass over aparticular point in the tissue at a given scan speed. Accordingly, thedwell time can be calculated as the optical energy beam width ordiameter divided by the scan speed.

Limiting irradiation times (dwell times) at a particular focal regionlocation can be achieved in various ways. In one exemplary embodiment,the radiation emitter arrangement 210 can be configured to providediscrete pulses of optical energy 150 into the focal regions 160. Theinterval between such pulses of optical energy can be, e.g., on theorder of about 50 milliseconds or more even if the location of the focalregion is moving through the skin tissue at a relatively slow speed of afew mm/s. These exemplary parameters can result in a distance betweenfocal regions 160 irradiated by successive pulses of, e.g., about 50-100microns, which can be greater than a width of the focal region 160itself. Accordingly, such general parameters can facilitate spatial andtemporal separation of the successive irradiated focal regions 160, suchthat local thermal relaxation can occur and buildup of excess heat canbe avoided. The spot size, pulse duration, and/or total pulse energy canbe selected based on the principles and guidelines described herein,using simple calculations, to provide a sufficient intensity within thefocal region 160 to generate a plasma in the pigmented structures 130while maintaining a sufficiently small dwell time (e.g. less than about1-2 ms) to avoid damaging unpigmented tissue.

In further exemplary embodiments of the present disclosure, the focusedradiation 150 can be scanned over a region of skin containingchromophores (such as, e.g., pigmented lesions or the like), such thatthe focal region(s) 160 may irradiate a large number of the pigmentedregions with sufficient intensity to form a plasma. Such scanning can beperformed with any of the embodiments described herein. The scanning canbe done manually, e.g., using a conventional method of translating ahandpiece over an area of skin to be treated. Alternatively, theapparatus 200 can optionally be coupled to a translating arrangementthat can be configured to automatically move the apparatus (or certaincomponents thereof) over an area of tissue to be treated. Such automatictranslation can be provided as a pre-set pattern or as a random orsemi-random path over the skin. In still further embodiments, one ormore of the optical components (e.g. the first and/or second lensarrangement 220, 230) and/or the radiation emitter arrangement can betranslated within the housing 250, such that the focal region(s) 160 cantranslate within the tissue while the housing 250 is held in a singleposition relative to the tissue.

Average scan speeds (or ranges of such speeds) can be determined basedon the general exemplary guidelines described herein. For example, for aparticular spot size (which can be determined primarily by theproperties of the optical arrangement), the local dwell (irradiation)time can be estimated as the spot size/width divided by thetranslational speed. As noted herein, such dwell time is preferably lessthan about 1-2 milliseconds to avoid local heat buildup and unwantedthermal damage of unpigmented tissue. Accordingly, a minimum scan speedcan be estimated as the width of the focal region 160 divided by 1millisecond. For example, a spot size of 10 microns (0.01 mm) wouldcorrespond to a minimum scan speed of 0.01 mm/0.001 seconds, or about 10mm/sec (1 cm/sec). Scan rates for line-focused beams (e.g., produced bydirecting an optical energy beam onto a cylindrical lens) can beestimated in a similar manner, e.g., where the width of the focal linecorresponds to the width of the focal region and the scan speed is in adirection perpendicular to the focal line, or for other scanningconfigurations.

For a pulsed laser source, the scan speed can be selected based at leastin part on the pulse energy and repetition rate, such that the totalenergy deposited into the target area can be controlled. For a pulsedlaser source, the local dwell time would correspond to the duration ofthe pulse, if the scan rate is low enough compared to the pulse durationthat the focal region does not move appreciably (e.g., it moves only afraction of the focal region width, such as half the spot width or less)during the pulse. As an example, with a pulse duration of 100 ns, arepetition rate of 50 khz, and a scan speed of 200 mm/s, there is apulse of energy deposited every 4 microns along the scan path, and thefocal region moves only about 0.02 microns during the pulse. Further,such scan speed and pulse repetition rate would lead to about, we wouldexpect about 2-3 pulses of energy to be received by a 10 um cell, eachpulse having a local dwell time of 100 ns.

A power output of the radiation emitter arrangement 210 can be selectedbased on several factors including, e.g., the optical energy wavelength,the number, sizes, and/or depths of the focal regions 160, opticalcharacteristics and geometry of the first and second lens arrangements220, 230, etc. The power output can be selected such that the fluence inthe focal region 160 is sufficiently high to damage pigmented cells 130that absorb the optical energy 150 for short exposure times, whilefluence at other depths (e.g., in the epidermis 110) is sufficiently lowto minimize or avoid unwanted damage there.

Based on some experimental observations, a local intensity (powerdensity) within the focal region 160 that may be sufficient to generatea plasma in melanin-containing structures (e.g., pigmented cells) can beabout 10{circumflex over ( )}10 W/cm² or more, for example, betweenabout 10{circumflex over ( )}10 W/cm² and 10{circumflex over ( )}11W/cm² for optical energy 150 having a wavelength of about 1060 nm. Acorresponding dwell time for local irradiation can be on the order of10{circumflex over ( )}−5 sec (e.g., 10 microseconds). This range ofeffective local beam intensity can increase with increasingscanning/translational speed of the focal region in the tissue, tomaintain a consistent local irradiation (dwell) time. Larger or smallerintensity values may also be provided when using faster or slower scanspeeds, in further exemplary embodiments. For example, a thermionicplasma in melanin may be initiated at lower power density, e.g., as lowas about 10{circumflex over ( )}8 W/cm², if other parameters such asabsorption efficiency (which depends in part on wavelength of theoptical energy) and energy density (which also depends in part on pulseduration) are selected appropriately. The local dwell time canpreferably remain on the order of tens of microseconds in suchembodiments.

Typical scan speeds for a handpiece that is manually translated over anarea of skin to be treated can be, e.g., on the order of about 5 mm/secto about 5 cm/sec. Such speeds correspond to traversing a distance of 5cm (about 2 inches) in about 1-10 seconds. Accordingly, for a handpiecethat is translated manually over the skin to irradiate portions of thedermis as described herein, the power output and focal geometry of theapparatus 200 can be selected to provide a power density and dwell timeat the irradiated locations within the dermis that is within the generalrange described herein.

Such exemplary power calculations can be based on the entire output ofthe laser diode being focused into one focal region. If the output froma single source of optical energy is focused onto a plurality of focalregions (e.g., when using an optical splitter or a wide beam directedonto a plurality of micro-lenses), then the power output of the opticalenergy source should be multiplied by the number of focal spots 160 toachieve the same power density within each focal region 160. Opticalenergy 150 can be provided as a continuous wave (CW) or optionally as aplurality of pulses. Alternatively, a plurality of optical energysources (e.g. laser diodes or the like) can be provided to generate aplurality of irradiated focal regions 160 simultaneously, with theappropriate power level for each optical energy source being estimatedas described above. In certain embodiments, if one or more opticalenergy beams are scanned over the focusing lens arrangement 230, thepower of the optical energy source can be selected based on the lensproperties, scan speed, etc. to provide power densities and dwell timesat pigmented locations of the tissue irradiated by the focal regions 160that are within the general ranges described herein.

In certain exemplary embodiments of the present disclosure, theradiation emitter arrangement 210 can include a plurality of opticalenergy emitters (e.g., laser diodes or lasers with separate waveguides).Such emitters can be provided in a linear array, such that they liesubstantially along one or more straight lines. In further exemplaryembodiments, the emitters can be arranged in a two-dimensional pattern,which can provide further patterns of optical energy 150 directed ontothe first lens arrangement 220. As described above, the power output ofeach emitter can be selected using a routine calculation based on thefocal spot size and scan speed to generate a local power density anddwell time for each focal zone 160 that is within the preferred rangedescribed herein.

The apparatus 200 shown in FIG. 2 illustrates one exemplaryconfiguration, and other embodiments using various combinations and/orconfigurations of similar components can also be used in furtherembodiments. For example, different numbers and/or types of opticalarrangements 220, 230 and/or emitter arrangements 210 can be used toprovide irradiation characteristics and focal regions 160 within thedermis 120 as described herein. In certain embodiments, the apparatus200 can be provided in a shape factor similar to that of a handheldrazor, with the radiation emitter arrangement 210 provided as one ormore laser diodes, optical arrangements 220, 230 provided in the “head”of the razor, and a power source (e.g. one or more conventional alkalinecells or the like) provided in the handle. Other form factors can alsobe used in further embodiments of the disclosure such as, e.g.,apparatus shapes that are more suitable for being translated by amotorized or automated translating apparatus.

One or more exemplary parameters of the apparatus 200 can be selectedand/or adjusted once the other ones are known to provide effectiveirradiation of the pigmented cells 130 to selectively form a plasma atthe pigmented regions, as described herein. For example, the exemplaryapparatus 200 having known geometry (e.g. spot size or focal line width,and NA) of the lens arrangements 220, 230 (and internal scanning speedof optical energy beams, if present), and a particular wavelength ofoptical energy 150 can be provided. The power of the optical energysource(s) can then be selected based on a target range of scanningspeeds of the apparatus 200 over the area to be treated to achieveappropriate local power densities and dwell times. For example, theexemplary apparatus 200 can be traversed over an area of tissue at aspeed between about 1-5 cm/s, which corresponds approximately to thespeed at which a conventional razor is traversed over skin duringshaving. Using these exemplary parameters and the number of passes to bemade over the treatment area, the local dwell time of the focalregion(s) 160 can be estimated, and a power output of the radiationemitter arrangement 210 can then be selected or adjusted to provide aneffective local power density within the focal region 160 as describedherein. Such calculations are routine and can be done by a person ofordinary skill in the art.

In still further exemplary embodiments, two consecutive pulses can beused to selectively form a plasma at or proximal to a chromophore asdescribed herein. For example, a laser having a modulated laserintensity can be used, or two or more lasers having different parametersand focused to the same region, can be used to selectively initiatethermionic emission at a chromophore under a first set of local energyconditions, and subsequently “pump” the thermal electrons under a secondset of local energy conditions to produce the local plasma. Theabsorptive heating of melanin is a linear process, whereas pumping ofthe thermal electrons into an electron avalanche to form and sustain aplasma is a non-linear process. The thermal relaxation time of amelanosome, the primary structure that biological melanin is associatedwith in nature, is several hundred nanoseconds. The laser used toselectively produce a plasma in tissue, as described in certainembodiments herein, can have a pulse duration on the order of about 100ns, which is less than the thermal relaxation time for melanosomes.These timescales allow the melanosomes to be efficiently heated toinduce emission of thermal electrons, but operate well above the shortfemto- and pico-second ranges associated with dielectric breakdown. Thethermal relaxation of time of a pigmented cell is much longer, about10-100 μs.

Accordingly, based on the principles described herein, a laser pulsehaving a duration on the order of, e.g., 10 μs, could be used toselectively heat the pigmented cells to liberate some electrons viathermionic emission. A second optical energy pulse having appropriateparameters, as described herein, including a pulse duration on the orderof approximately 100 ns, could then be focused to irradiate the samepigmented cells and “pump” the released electrons before they relax andrejoin the locally ionized atoms or molecules, thereby forming a plasmaat the pigmented cells. Other pigmented targets located in the tissue,which may be external to cells, can also be irradiated to promoteselective absorption of energy and plasma generation.

In further exemplary embodiments of the present disclosure, a method forselectively producing plasma in pigmented regions of biological tissuecan be provided. The exemplary method can include directing and focusingelectromagnetic radiation 150 as described herein onto a plurality offocal regions 160 within the dermis 120 using an optical arrangement,such that the optical energy 150 is selectively absorbed by pigmentedregions 130 to generate some local ionization via thermionic emission ofelectrons. The beam intensity and local dwell time should besufficiently large to allow further energy to be absorbed by the freedelectrons, leading to further ionization by the excited electrons and asubsequent chain reaction (sometimes referred to in physics literatureas an “electron avalanche”) to form a plasma in the tissue.

Example 1

An animal study using an exemplary spot-focused laser device and modelsystem were used to test the efficacy of selective plasma formation inskin tissue using optical radiation. The study was performed on a femaleYucatan pig, as described below.

First, a deep-melasma condition was simulated by tattooing the dermisusing a melanin-based ink. The ink was prepared by mixing syntheticmelanin at a concentration of 20 mg/mL in a 50:50 saline/glycerolsolution. The resulting suspension was then agitated prior to beinginjected into approximately 1″×1″ test sites on the animal subject usinga standard tattoo gun, at a depth range of about 200-400 μm. Each testsite was provided with a darker black tattooed border using India ink tofacilitate identification of the various test sites.

An exemplary melasma treatment system was constructed based on exemplaryembodiments of the present disclosure described herein, which includes aQ-switched 1060 nm Yb-fiber laser with an average power of up to 10 W,operating at a pulse rate between 20 kHz and 100 kHz and a pulseduration of 100 ns. The laser was mounted on an x-y scanning platform.The measured focal spot size was approximately 4 μm. The collimatedoutput of the fiber laser was focused with an effective focal length of8 mm and a numerical aperture (NA) of 0.5.

A table of exemplary scanning parameters used to establish selectiveformation of plasmas in biological tissue is shown below in Table 1. Thelaser power was either 2 or 4 W, the raster line speed of the focal spotwas between 50 and 800 mm/s, the spacing between adjacent raster scanlines (which determines the overall coverage of each plane) rangedbetween 0.0125 and 0.05 mm. These parameter ranges were selected tocover a range in which some parameter sets produced a plasma, asevidenced by visible white sparks and audible popping sounds, and othersdid not. In general, plasma formation was not observed at scanning ratesof about 400 mm/s or more at these power levels.

The energy and scanning parameters shown in Table 1 represent exemplarytesting parameters used to evaluate the functioning of the prototypeapparatus described herein and to refine approximate parametercombinations for further study. Plasma formation was observed at scanspeeds less than about 100 mm/s for these power levels of 2 and 4 watts,whereas higher scan speeds did not generally result in observed plasmaformation.

Exemplary system parameters and procedure for producing visible effectsin biological tissue were as follows: The scanner was used to scan thelaser beam over a 1 cm×1 cm area within each melanin-tattooed test siteat a speed of 200 mm/s, which tended to produce evidence of plasmaformation. Different test scans were run with laser power outputs of 1W, 2 W, 3 W, 4 W, and 10 W. Multiple depths were scanned in each testsite, with the beam focal region scanned in a raster scan pattern at asingle focal depth before changing the focal depth and repeating theraster scan pattern. Most test treatments were performed at a 50 kHzpulse repetition rate, with some tests performed at a 20 kHz forcomparison. A schematic illustration of the scan pattern used for 3separate depths is shown in FIG. 4.

The distance between successive focal-depth planes was about 50 μm, anda ‘rest’ interval of about 4-5 minutes was provided between area rasterscans at each focal depth, to allow the tissue to cool. Betweensuccessive scans at different depths, rubbing alcohol was sprayed ontothe treated area and massaged in order to help dissipate the whitecavitation that was observed to form when the laser interacts withtissue layers containing melanin. Without such alcohol rubbing, thiswhite film was observed to take significantly longer to dissipate on itsown (e.g., about 10-15 minutes as compared to about 4-5 minutes with thealcohol rubbing).

Exemplary results of an exemplary treatment of a melanin-tattooed testsite in accordance with exemplary embodiments of the present disclosureare shown in FIG. 5. The Yb-fiber laser was set to an average of 2 Wpower output, with a pulse repetition rate of 50 kHz and a scan speed of200 mm/s. The distance between adjacent raster lines was 12.5 μm, and 6different depths were irradiated, ranging from 300 to 550 μm at 50-μmintervals.

For example, image 510 provided in FIG. 5 shows the test site just priorto scanning with the laser apparatus, and image 512 shows the test sitejust after the scan was completed. Images 514, 516, 518, and 520illustrate the appearance of the test site at 2 hours, 1 day, 1 week,and 4 weeks, respectively, after the irradiation treatment. Immediatelightening of the irradiated region was observed post-treatment, and itpersisted 4 weeks later.

TABLE 1 Exemplary parameters for raster scanning of the optical energybeam focal region over each constant-depth plane within the test areas.The rectangular raster pattern is illustrated in FIG. 4. Yb-fiber laser(1060 nm) Relative Power Speed Spacing Energy Time (watt) (mm/s) (mm)Coverage Layers Delivered (min) 2  50 0.05  25% 2  50% 6.666667 2 1000.0125 100% 2 100% 20.8 4 400 0.0125 100% 2  50% 16 4 400 0.025  50% 2 25% 8 4 400 0.05  25% 2 12.5%  4 4 800 0.0125 100% 2  50% 13.3 4 8000.025  50% 2  25% 6.66 4 800 0.05  25% 2 12.5%  3.33 2 800 0.0125 100% 2 25% 13.33 2 800 0.025  50% 2 12.5%  6.66 2 800 0.05  25% 2 6.25%  3.33Total 102.13 Time

Example 2

FIG. 6 shows a further scanned melanin-tattooed test site that wasirradiated using the general scan parameters indicated above (e.g., ascan rate of 200 mm/s, a repetition rate of 50 kHz, and six (6)sequential scanned layer depths of 550, 500, 450, 400, 350, and 300 μm,and a distance between adjacent scan lines in each plane of 25 μm), witha fiber laser output of 1 W, at various times, in accordance withfurther embodiments of the present disclosure. Image 610 in FIG. 6 showsthe test site just prior to a scanned irradiation using the laserapparatus, and image 612 shows the test site just after the scan wascompleted. Images 614, 616, 618, 620, and 622 illustrate the appearanceof the test site 610 at 1 hour, 3 days, 1 week, 2 weeks, and 4 weeks,respectively, after the irradiation treatment. No plasma formation wasobserved at this lower power output level.

Example 3

FIGS. 7A and 7B show images of a melanin-tattooed test site that wasscanned twice, over two sessions spaced two weeks apart. Bothirradiation treatments used a fiber laser with an average power outputof 6 W and a pulse repetition rate of 20 kHz. The first scan sessiontargeted more superficial layers (300 um to 550 um) whereas the secondscan session targeted deeper layers (550 um to 850 um).

In particular, FIG. 7A illustrates exemplary results of the firstscanned irradiation treatment. Image 710 in FIG. 7A shows the test sitejust prior to the first scanned irradiation using the laser apparatus,image 712 shows the test site just after the first scan was completed,and image 714 shows the test site 24 hours after the first scan wascompleted. Images 716, 718, and 720 provided in FIG. 7B show theappearance of the test site 710 just prior to, immediately following,and 24 hours following the second irradiation treatment, respectively.This second deeper irradiation treatment was performed 2 weeks after thefirst scanning treatment. Plasma formation (in the form of small sparksand popping noises) was observed at this intermediate power outputlevel.

Example 4

More immediate skin whitening effects were observed at higher poweroutputs. For example, a tattooed test site was scanned at a fiber laserpower output of 10 W, with other scan parameters matching those used toobtain the results illustrated in FIGS. 7A and 7B. Whitening of thescanned area in the center of the tattooed region was observedimmediately following the scanning procedure, as shown in FIG. 8A. Theobserved plasma was more intense at this higher power level, indicatinga correlation between (peak) power level and plasma intensity underconditions where plasmas are generated selectively in tissue.

General guidelines for generating plasma selectively at the sites ofmelanin chromophores can be estimated from the various test scansperformed. For example, with a spot size of 4 um, an average fiber laserpower output of 4 W, a pulse duration of 100 ns, and a repetition rateof 50 kHz (which produced visible plasma effects with some whitening ofthe skin at later times, as shown in FIG. 5), the local peak powerdensity can be calculated as approximately 6.37×10⁹ W/cm², and the peakpower is about 800 W.

At the higher end of applied power density (e.g., 10 W average power and20 kHz repetition rate, corresponding to the conditions of FIG. 8A), thepeak power density is about 3.98×10¹⁰ W/cm² and the corresponding peakpower is about 5 kW. These higher power levels led to more immediatewhitening of the tissue and a more intense visible plasma.

For the scan speeds used (typically 200 mm/s), the pulse duration of 100ns is sufficiently short that the focal spot does not move by more thana few nanometers before the pulse is switched off. At a scan speed of200 mm/s, each 10 mm scan line in the takes 0.05 seconds to complete. Ata pulse rate of 50 kHz, there are 2500 pulses per scan line, such thatthe distance between successive pulses is about 4 μm. Because the spotwidth used is 4 μm and the distance between the centers of adjacentpulses along the scan line is also 4 μm, this set of scan parametersgenerates an essentially continuous train of pulses that are justtouching each other (e.g., a continuous scanned line with littleoverlap). Accordingly, for melanophages or other chromophore siteshaving a diameter or width of about 10 μm, each melanophage would besubjected to roughly 2-3 pulses. With the exemplary pulse duration of100 ns, the total local dwell (exposure) time for such melanophages isabout 250 ns.

Example 5

FIG. 8B shows a set of images of a pig skin test site that was scannedusing a laser beam having a scan rate of 200 mm/s along a scan line, arepetition rate of 20 kHz, a wavelength of about 1060 nm, a pulseduration of about 100 nanoseconds, and an output power of 8 W. Thedistance between adjacent scan lines was about 25 μm. The focal regionof the laser beam was located approximately at the surface of the nativeskin. Image 810 shows the test site just before treatment, image 812shows the test site immediately after treatment, and image 814 shows thetest site 24 hours after treatment. Several biopsy samples of thetreated skin tissue that were taken can be seen in image 814. Underthese irradiation conditions, plasma formation was observed in the pigskin due to irradiation of the laser beam.

Example 6

FIG. 8C illustrates an exemplary image of a biopsy taken from the nativeskin test site taken by an electron microscope (EM) described in Example5 and shown in FIG. 8B. An obliterated cell 820 and unaltered cells 830can be observed. The obliterated cell 820 contains melanin and theobliteration is believed to have resulted from treatment by the laserbeam. The unaltered cells 830 are located as close as about 5 microns tothe obliterated cell 820. The unaltered cells 830 contain generally nomelanin, and are believed to have remained vital after treatment.

Example 7

FIG. 9 shows a cross-sectional view of a system 910 for generating anddetecting plasma formation in vivo in a tissue sample (e.g., human skin,sow skin, and the like) according to an exemplary embodiment of thepresent disclosure that was used in Examples 8-10 described herein. Theexemplary system 910 includes an optical element 914 that receives acollimated laser beam 912 and directs the collimated laser beam towardsa focusing arrangement 916 (e.g., a lens). The focusing arrangement 916focuses the laser beam 912 to a focal region 920 which is located in thetissue sample 918. The focused laser beam generates thermionic plasma atthe focal region 920 using thermionic plasma initiation. The thermionicplasma generates a further radiation 913. The optical element 914receives the plasma-generated radiation 913, and transmits it towards aspectrometer. A fiber coupler 922 receives the radiation 913 and directsit to a spectrometer via a fiber optic.

The optical element 914 can be selected based on the spectralcomposition of the laser beam 912 and emitted radiation 913. Forexample, exemplary properties of the optical element 914 can be selectedto substantially reflect spectral components of the laser beam 912, andsubstantially transmit spectral components of the emitted radiation 913.In one exemplary embodiment, the laser beam 912 can include 1060 nmwavelength. The corresponding optical element 914 that was used is aThorlabs NB1-K14 Nd:YAG Mirror that reflects wavelengths ranging fromabout 1047 nm to about 1064 nm. The reflected portion of the laser beam912 is imaged and focused by focusing arrangement 916. The used in thisexemplary apparatus 900 includes a Thorlabs C240TME-C mounteddiffraction-limited aspheric lens, which has a focal length of 8 mm anda numerical aperture (NA) of about 0.5. The laser beam 912 is focused toa focal region 920 that can be located in the tissue 918, based on thedistance between the focusing arrangement 916 and the tissue 918.Thermionic plasma can be generated in portions of the focal region thatinclude a target chromophore (e.g., melanin tattoo, carbon tattoo, clearacrylic plastic sample, tinted acrylic plastic sample, and the like).

Radiation 913 emitted from the plasma generated in the tissue 918 at thefocal region 920 can be imaged by the focusing arrangement 916, andtransmitted by the optical element 914 to impinge on a first end of afiber optic (not shown) by a fiber coupler 922. The fiber coupler usedin apparatus 900 is a Thorlabs PAF-SMA-7-A fiber collimator and coupler.A second end of the fiber optic is coupled to an Ocean Optics HR2000+ ESspectrometer. A notch filter (not shown) is included between the opticalelement 914 and the fiber coupler 922 to block/dissipate spectralcomponents of the emitted radiation 913 that have wavelengthssubstantially similar to the spectral component of the laser beam 912.

The tissue sample 918 can be mounted on a motorized stage that can bemoved independently along the x, y, and z axes. By such exemplarymovement, the motorized stage can place a particular portion of thetissue sample 918 into the focal region 920 of the focused laser beam912. For example, a working distance between the tissue sample 918 andthe focus optic 916 can be varied (e.g., along the z-axis) to control adepth of the focal region 920 of the laser beam 912 within the tissuesample 918. The motorized stage also moves in the x-y plane and can movecertain portions of the tissue sample 918 (e.g., a portion that includesa target chromophore) into the focal region 920.

FIG. 10A illustrates an exemplary plot of the intensity spectrumdetected by the spectrometer of the system 900 described above. In thisexample, the tissue sample 918 that includes a melanin tattoo is placedon the motorized stage beneath the focus optic 916. The focal region 920is provide about 0.2 mm below the surface of the tissue sample 918. Themelanin tattoo is located approximately between a quarter of amillimeter and a millimeter below the dermis of the skin sample.

The horizontal axis provided in FIG. 10A represents wavelength (innanometers) of the detected radiation. The vertical axis representsintensity of the detected radiation at each wavelength. Two spectra aredisplayed in FIG. 10A, i.e., a melanin tattoo spectrum 1014, and a bareskin spectrum 1016. The melanin tattoo spectrum 1014 represents ameasurement taken during irradiation of the tissue sample at thelocation of the melanin tattoo. The bare skin spectrum 1016 represents ameasurement taken during irradiation of the sample away from thelocation of the melanin tattoo. The melanin tattoo spectrum 1014 shows apresence of a broad-spectrum light during irradiation centered at about600 nm and covering the visible spectrum. In contrast, the bare skinspectrum 1016 has relatively lower intensities for visible light (e.g.,for wavelengths ranging from about 500 nm to about 800 nm).

The operating parameters of the exemplary system 900 for detection ofthe intensity plot in FIG. 10A can be as follows. For example, the laserbeam 912 has a repetition rate of 20 KHz, and includes laser pulseshaving a time duration of about 100 nanoseconds and pulse energy ofabout 0.5 mJ per pulse. The treatment site is treated with a scan rate(e.g., x-y or lateral speed of the laser beam 912 over the test site) ofabout 100 mm/s along multiple scan lines. The spectrometer was adjustedto capture light over a 5000 millisecond period, and was triggered whenan irradiation impinges on the spectrometer.

FIG. 10B shows a photomicrograph image of a section of the tissue samplecontaining melanin tattoo that was irradiated to obtain the intensityspectrum 1014 in FIG. 10A. Tissue surface 950 is shown at the top of theimage of FIG. 10B. An epidermis-dermis junction 952 demarcates theepidermis and dermis layers of the skin. Melanin globules 954 present inthe dermis constitute the melanin tattoo.

Example 8

FIG. 11 illustrates an exemplary plot of further intensity spectradetected by the spectrometer of the system 900 described in Example 7.In this example, the tissue sample 918 included a carbon tattoo and wasplaced on the motorized stage beneath the focusing arrangement 916. Thefocal region 920 was located about 0.2 mm below the surface of thetissue sample 918. The carbon tattoo was located between approximately aquarter of a millimeter and a millimeter below the dermis of the skinsample.

The horizontal axis provided in FIG. 11 represents wavelength (innanometers) of the detected radiation. The vertical axis representsintensity of the detected radiation at each corresponding wavelength.Two spectra are displayed in FIG. 11: a spectrum 1114 obtained duringirradiation of a sample region containing a carbon tattoo, and aspectrum 1116 obtained during irradiation of a sample region that didnot have any carbon tattoo present. The carbon tattoo spectrum 1114shows a presence of a broad-spectrum of emitted light during irradiationcentered at about 600 nm and covering the visible spectrum. The bareskin spectrum 1116 has relatively lower intensities for visible light(e.g., for wavelengths ranging from about 400 nm to about 800 nm).

The operating parameters of the system 900 for detection of theintensity plot shown in FIG. 11 are as follows. The laser beam 912 has arepetition rate of about 20 KHz, and includes laser pulses having a timeduration of about 100 nanoseconds and pulse energy of about 0.5 mJ perpulse. The treatment site was treated with a scan rate (e.g., lateral orx-y speed of the laser beam 912 along the test site) of about 100 mm/salong multiple scan lines. The spectrometer was adjusted to capturelight over a 5000 millisecond period, and was triggered when anirradiation impinges on the spectrometer.

Example 9

FIG. 12 illustrates exemplary images of an exemplary test site atvarious stages of treatment using the treatment system 900 described inExample 7. Image 1210 illustrates the test site prior to the treatmentthat includes a region 1209 for treatment and a second control region1211. In these images, the region to be treated (e.g., region 1209having hyperpigmentation resulting from post-acne scarring) is generallyplaced in the center of the test site. The control region 1211 is leftuntreated and is located in the top right corner of the test site.

The treatment region 1209 was scanned using system 900 with a laser beamhaving an output power of 10 W, a wavelength of about 1060 nm, a pulseduration of about 100 nanoseconds and a repetition rate of 20 kHz. Thetreatment region 1209 was treated with a scan rate (e.g., lateral speedof the laser beam along the test site) of about 100 mm/s along multiplescan lines. The distance between the scan lines was about 25 μm.Additionally, six layers of the test site having varying depths (e.g.,300, 350, 400, 450, 500, and 550 μm from the surface of the test site)were scanned.

Images 1212-1220 illustrate the overall treatment site at various timesafter treatment. Image 1212 shows the test site immediately aftertreatment. Image 1214 shows the test site 24 hours after treatment.Images 1216, 1218, and 1220 show the test site at 1 week, 1 month, and 3months after treatment, respectively. Observation of images 1212-1220suggests that the color of the treatment region 1209 gradually fadeswith the passage of time. Additionally, the color of the control region1211 does not appear to fade as compared to the treatment region 1209during the same period. Further, a surface texture of the treatmentregion 1209 appears to smoothen after treatment. The surface texture ofthe treatment region 1209 appears generally as smooth as the surroundingskin 3 months after treatment (image 1220). However, a surface textureof the control region 1211 remains generally unchanged in images takenafter treatment. As evidenced by the images of FIG. 12, the treatmentsite does not appear to be adversely affected (e.g., due to injuries) bythe treatment. Treatments using average laser beam power outputs of upto 20 W (together with other parameter ranges described herein) appearto be safe and not generate unwanted damage in the skin tissue.

Example 10

FIG. 13 shows exemplary images of an exemplary test site at variousstages of treatment by the treatment system 900 described in Example 7.Image 1310 illustrates the test site prior to the treatment thatincludes a region 1309. The region to be treated (e.g., region 1309having hyperpigmentation resulting from post-acne scarring) is generallyplaced in the center of test site. The test site was irradiated usingthe following parameters. The laser beam had an output power of 20 W, awavelength of about 1060 nm, a pulse duration of about 100 nanosecondsand a repetition rate of 20 kHz. The treatment site was treated with ascan rate (e.g., lateral speed of the laser beam over the test site) ofabout 100 mm/s along multiple scan lines. The distance between the scanlines was about 25 μm. Additionally the test site was scannedsuccessively at 8 different depths (e.g., 200, 250, 300, 350, 400, 450,500, and 550 μm from the surface of the test site).

Images 1312-1318 show the treatment site at various times aftertreatment. Image 1312 shows the test site immediately after treatment.Images 1314, 1316, and 1318 show the test site 24 hours, 1 week, and 1month after the irradiation treatment, respectively. Images 1312-1318suggest that the color of the treatment region 1309 gradually fades withthe passage of time. Additionally, a surface texture of the treatmentregion 1309 appears to smoothen after treatment. The surface texture ofthe treatment region 1309 is generally as smooth as the surrounding skin1 month after treatment. Although some redness was observed immediatelypost-treatment in image 1312, the redness was not present in the 24-hourimage 1314.

The exemplary parameters and calculations described in the Examplesherein and in other parts of the present disclosure can be used todetermine other parameter combinations that can also generate selectiveplasma formation at chromophore sites, using conventional geometric andenergy relationships. For example, the amount of energy delivered toeach location in the tissue can be reduced by half by doubling the scanspeed or by reducing the average laser power output by half. However,the faster scan speed reduces the local dwell (exposure) time in half,whereas reducing the average laser output power leaves the dwell timeunaffected. Doubling the spot size/diameter (with all other laserparameters kept fixed) will reduce the local power and energy densitiesby a factor of 4. Such larger spot sizes (at a fixed scan speed) willalso double the local dwell time at a location in the tissue, becausethe wider spot will take twice as long to pass through a particularpoint in the tissue.

Accordingly, further combinations of pulse durations, power output,pulse frequency, scan rate, focal spot sizes, etc. that lead toselective plasma formation can be readily estimated when one or moreparameters are varied within the exemplary sets of values presentedherein. Parameters that should remain close to those presented here toachieve similar effects in tissue include local power and energydensities, and local dwell times. Further variation of such parametersto account for changes in other factors such as different wavelengths orother chromophores can also be estimated, e.g., by accounting for thechanges in energy absorption efficiency by the chromophore, etc.

Further, although the examples herein are described primarily withrespect to selective plasma formation at chromophore sites in biologicaltissues such as skin, similar principles can be applied to selectivelygenerate plasmas in other irradiated tissues (e.g. brain tissue, etc.)and in other materials, e.g. non-biological materials that haverelatively weak absorption coefficients and contain regions ofhighly-absorbing chromophores.

The foregoing merely illustrates the principles of the presentdisclosure. Various modifications and alterations to the describedembodiments will be apparent to those skilled in the art in view of theteachings herein. It will thus be appreciated that those skilled in theart will be able to devise numerous techniques which, although notexplicitly described herein, embody the principles of the presentdisclosure and are thus within the spirit and scope of the presentdisclosure. All patents and publications cited herein are incorporatedherein by reference in their entireties.

1-22. (canceled)
 23. A method, comprising: emitting, by a laser systemincluding at least one laser, at least one laser beam having ananosecond pulse duration; focusing, by an optical system including atleast one lens, the at least one laser beam to a focal region at aselected distance from a surface of a tissue including pigmented andunpigmented regions; and controlling, using a control arrangement, thelaser system and the optical system to cause an irradiation energytransferred to the focal region of the at least one laser beam at awavelength that is selectively absorbed by the pigmented region of thetissue, wherein the at least one laser beam generates a plasma locallyat the pigmented regions of the tissue when the focal region overlapswith the pigmented regions, thereby causing damage to the pigmentedregions of the tissue within the focal region, and wherein the at leastone laser beam avoids damage at the unpigmented regions of the tissueand when the focal region does not overlap with the pigmented region andoverlaps with the unpigmented region.
 24. The method of claim 23,wherein the plasma is a thermionic plasma, and wherein the generation ofthe thermionic plasma (i) causes damage to the pigmented regions of thetissue within the focal region when the focal region overlaps with thepigmented regions, and (ii) avoids a generation of the thermionic plasmaat the unpigmented regions of the tissue and avoids damage at theunpigmented regions of the tissue when the focal region does not overlapwith the pigmented region and overlaps with the unpigmented region. 25.The method of claim 23, wherein a numerical aperture of the at least onelens is between 0.5 and 0.9.
 26. The method of claim 23, wherein the atleast one laser beam has a wavelength in the range of about 600 nm toabout 1100 nm when measured in air.
 27. The method of claim 23, whereina peak intensity of the at least one laser beam is at least about 108W/cm² in the focal region.
 28. The method of claim 23, wherein the focalregion is located within the dermis.
 29. The method of claim 23, whereinthe at least one laser beam comprises (i) a first laser pulse configuredto generate a thermionic emission of electrons, and (ii) a second laserpulse configured to generate the plasma that is a thermionic plasma. 30.The method of claim 23, wherein a spot size of the focal region is inthe range of about 5 μm to about 100 μm when measured in air.
 31. Themethod of claim 23, wherein the at least one lens is configured to varythe selected distance of the focal region with respect to the surface ofthe tissue.
 32. The method of claim 31, wherein the selected distance ofthe focal region from the surface of the tissue is in the range of about5 μm to about 1000 μm.
 33. The method of claim 23, wherein the at leastone lens comprises a plurality of micro-lenses.
 34. The method of claim33, further comprising directing a single laser beam over at least oneportion of the plurality of micro-lenses to produce a plurality of focalregions simultaneously.
 35. The method of claim 33, further comprisingdirecting a single laser beam over at least a portion of the pluralityof micro-lenses to produce a plurality of focal regionsnon-simultaneously.
 36. The method of claim 33, further comprising:emitting a plurality of laser beams; and directing at least one of theplurality of laser beams on one or more of the plurality ofmicro-lenses.
 37. The method of claim 23, wherein the pigmented regionsof the tissue comprise a chromophore.
 38. The method of claim 37,wherein the chromophore comprises at least one of melanin, tattoo inks,hemoglobin, sebaceous glands, subcutaneous fat, hair bulb, lipids incell membrane, fat surrounding organs, vessels, or drug components. 39.The method of claim 23, further comprising detecting, by one or moresensors, one or more of a velocity or a position of an apparatus, thatincludes the laser system and the optical system, relative to thesurface of the tissue.
 40. The method of claim 39, further comprising:receiving, by a feedback control configuration, data characterizing theone or more of the velocity or the position detected by the one or moresensors; and controlling, by the feedback control configuration, atleast one of a pulse duration, a pulse frequency or a pulse energy ofthe at least one laser beam.
 41. The method of claim 23, furthercomprising controlling, by the laser system, a time interval betweentemporally adjacent laser pulses of the at least one laser beam suchthat a travel time for a movement of the focal region from a firstlocation in the tissue to a second location in the tissue is less thanthe time interval.
 42. The method of claim 41, wherein the time intervalbetween the temporally adjacent laser pulses is less than 50milliseconds.
 43. A method, comprising: emitting, by a laser system thatincludes at least one q-switched laser, at least one laser beam;focusing, by an optical system that includes at least one lens, the atleast one laser beam to a focal region at a selected distance from asurface of a tissue that includes pigmented and unpigmented regions; andcontrolling, using a control arrangement, the laser system and theoptical system to cause an irradiation energy transferred to the focalregion of the at least one laser beam at a wavelength that isselectively absorbed by the pigmented region of the tissue, wherein,when the focal region overlaps with the pigmented regions, the at leastone laser beam generates a thermionic plasma locally at the pigmentedregions of the tissue, thereby causing damage to the pigmented region ofthe tissue within the focal region, and wherein, when the focal regiondoes not overlap with the pigmented regions and overlaps with theunpigmented region, the at least one laser beam avoids generation of thethermionic plasma damage at the unpigmented regions and avoids damage atthe unpigmented regions of the tissue.
 44. The method of claim 43,wherein a numerical aperture of the at least one lens is between 0.5 and0.9.
 45. The method of claim 43, wherein the at least one laser beam hasa wavelength in the range of about 600 nm to about 1100 nm when measuredin air.